Intravenous administration of tramadol

ABSTRACT

A method of treating pain, e.g., acute post-operative pain, by administering to a human patient(s) a therapeutically effective dose of tramadol intravenously in a dosing regimen which includes one or more loading doses administered at shortened intervals as compared to dosing at steady-state is disclosed. In certain embodiments, the dose of tramadol is from about 45 mg to about 80 mg and the second (and optionally) third doses are intravenously administered at intervals of from about 2 to about 3 hours, and thereafter the tramadol is intravenously administered at a dosing interval of about 4 to about 6 hours, until the patient no longer requires treatment with tramadol. In preferred embodiments, the intravenous dosing regimen provides a Cmax and AUC of tramadol is similar to the Cmax and AUC of an oral dose of 100 mg tramadol HCl given every 6 hours. In certain preferred embodiments, the dosing regimen comprises 50 mg IV tramadol at Hour 0, followed by 50 mg at Hour 2, 50 mg at hour 4, and 50 mg every 4 hours thereafter (e.g., until the patient no longer requires treatment with tramadol).

This application is a continuation-in-part of U.S. application Ser. No.15/163,111 filed May 24, 2016, which claims priority to U.S. ProvisionalApplication No. 62/271,107 filed on Dec. 22, 2015, the disclosures ofwhich are hereby incorporated by reference herein.

BACKGROUND OF THE INVENTION

Tramadol is a centrally acting synthetic analgesic with a dual mechanismof action attributed to the racemic form of the drug, comprised ofμ-opioid activity (binding to μ-opioid receptors and monoamine(serotonin and noradrenalin) reuptake inhibition. Tramadol is an analogof the phenanthrene group of opium alkaloids, which includes morphineand codeine, and is structurally related to these opioids (Grond S andSlabotzi A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43:879-923). Like codeine, there is a substitution of the methyl groupon the phenol ring that imparts a relatively weak affinity for opioidreceptors. (+)-Tramadol is a more potent inhibitor of serotonin uptake,while (−)-tramadol is a more potent inhibitor of norepinephrine uptake.The opioid-like activity of tramadol derives from low affinity bindingof the parent compound to μ-opioid receptors and higher affinity bindingof its main metabolite. Tramadol affinity to μ opioid receptors is about10 times weaker than codeine 60 times weaker than dextropropoxyphene and6,000 times weaker than morphine. The active metaboliteO-desmethyltramadol (M1) possesses a higher affinity to the μ opioidreceptor than tramadol and displays analgesic activity (Leppert W,2009).

Tramadol was originally developed by the German pharmaceutical companyGrünenthal GmbH in the late 1970s and is marketed globally under thetrade names TRAMAL® and others outside of the United States. Theapproved doses of tramadol are 50 mg or 100 mg administered as a slowinjection every 4-6 hours (Tramadol Core Product Label, 2008). In theU.S., tramadol is approved by the Food and Drug Administration (FDA) andmarketed as an oral capsule/tablet for moderate to moderately severepain in adults. Tramadol was first approved in the US in April 1995under the trade name, ULTRAM® (Ortho-McNeil-Janssen Pharmaceuticals,Inc). Tramadol is also an active agent in an extended release product,Ultram® ER, and a combination product with acetaminophen, ULTRACET®. Inthe US, tramadol is only available as immediate release tablets orextended release tablets. Other tramadol formulations approved inseveral countries include tablets, capsules, effervescent powders, andsuppositories (Grond and Sablotzki, 2004; Rosenberg, 2009). The approvedintravenous regimen in India is an initial injection of 50 mg infusionover 2-3 min, followed by 50 mg every 10-20 minutes if necessary up to250 mg for the first hour. Maintenance doses are 50-100 mg every 4-6hours with a maximum dose of 600 mg daily (Tramadol, CIMS Data_India).

Postoperative pain management with tramadol has effectively utilized avariety of delivery methods, including bolus injection (IV or IM),continuous infusions and patient controlled analgesia (PCA) pumps, andvarious combinations of these methods (Scott and Perry, 2000; Grond andSablotzki, 2004). The potency ratio of IV tramadol to IV morphine isapproximately 1:10, while the ratio for IV fentanyl is 1:979 (Grond andSablotzki, 2004).

The “on-demand” analgesic efficacy of tramadol was compared to morphinein the 24-hour post-operative period for 523 patients undergoingabdominal surgery (Vickers M D, Paravicini D. Comparison of tramadolwith morphine for post-operative pain following abdominal surgery. Eur JAnesthesiol. 1995; 12: 265-71). Patients who reported post-operativepain received an initial dose (either tramadol 100 mg or morphine 5 mgi.v.) and, if necessary, repeat i.v. or i.m. doses of tramadol 50 mg ormorphine 5 mg on demand over the first 90 minutes. Further doses up to atotal of 400 mg tramadol or 40 mg morphine could then be given after 90minutes up to 24 hours after the first dose of study medication. Theprimary efficacy parameter was the responder rate (no or slight pain)within the first 90 minutes of treatment. Responder rates were 72.6% fortramadol and 81.2% for morphine, which were statistically equivalent andwithin the predefined range of ±10%. Mean cumulative doses were 188.2 mgfor the first 90 minutes and 157.1 mg for the subsequent 22.5 hours inthe tramadol group and 13.9 mg and 18.4 mg, respectively in the morphinegroup. The main adverse events were gastrointestinal in both groups,with mild nausea, dry mouth, vomiting, dyspepsia and hiccups reportedmost frequently.

The analgesic effect of continuous infusion of tramadol was compared torepeated bolus administration in 135 patients undergoing abdominalsurgery (Rud U, Fischer M V, Mewes R, Paravcini D., “PostoperativeAnalgesie mit Tramadol Kontinuierliche Infusion versus repetitive”(Postoperative analgesia with tramadol. Continuous infusion versusrepetitive bolus administration), Bolusgabe Anaesthesist. 1994;43:316-321. (German)). Patients were randomized at the time of the firstrequest for pain treatment. All patients received a loading dose oftramadol 100 mg i.v. Subsequent treatment was administered in adouble-blind manner; patients in the infusion group were given acontinuous infusion of tramadol 12 mg/h for 24 hours, whereas patientsin the bolus group received placebo infusion. In both groups, additionalbolus doses of tramadol 50 mg i.v. were given as required. Pain reliefwas monitored by means of a visual analog scale (VAS) up to 6 hoursafter surgery. The number of additional boluses and the amount oftramadol administered at 6 hours and 24 hours was also used to assessanalgesic efficacy. More patients in the infusion group assessed theirpain relief as excellent or good compared to the bolus group (76.5% vs65.6%). Only a few patients complained of insufficient analgesia, withmore patients in the bolus group reporting inadequate pain relief thanin the infusion group (7.5% vs 4.4%). A higher percentage of patients inthe bolus group required two or more boluses compared to the infusiongroup (59.7% vs 30.8%). After 6 hours, the average tramadol consumptionwas 223.5±53.7 mg in the infusion group and 176.6±63.1 mg in the bolusgroup (p≤0.05). After 24 hours, tramadol consumption was 449.5±66.0 mgand 201.6±83.9 mg (p≤0.001), respectively. Adverse events were reportedby 25% of patients in both groups, with no significant differences andno patient terminated the trial for an adverse event. There were nosignificant effects on blood pressure or heart rate. The authorsconcluded that continuous infusion was more effective in the first 6hours after surgery. However, excess consumption by the infusion groupwas statistically greater than the bolus group at both 6 hours and 24hours post-surgery.

Intermittent bolus and continuous infusion of tramadol were evaluated ina postoperative study of 35 patients undergoing major abdominalgynecologic surgery (Chrubasik J, Buzina M, Schulte-Monting J,Atanassoff P, Alon E. Intravenous tramadol for post-operativepain-comparison of intermittent dose regimens with and withoutmaintenance infusion. Eur J Anaesthesiol. 1992; 9:23-28). The study wasrandomized and double-blind and used tramadol infusion 15 mg/h orsaline. Additional boluses of tramadol 100 mg were given as requested.The patients in the infusion group required 60% less tramadol on demand(p<0.01) and had better pain relief (p<0.05), as assessed by VAS, thanthe group that received the saline infusion. Total tramadol consumption,however, was about 30% higher in the infusion group (p<0.05) and wasassociated with and increased incidence of minor adverse events.Tramadol was ineffective as pain relief within 2 hours of the beginningof treatment in 6% of the infusion group and 20% of the bolus group.Thus, continuous infusion was preferred to “on-demand” bolus treatment.

A meta-analysis of nine randomized, controlled trials indicated thattramadol was as effective as other opioids, including morphine, forcontrol of postoperative pain (Scott and Perry, 2000). Pain in thesepatients was described as moderate to severe, with initial postoperativepain reported as >60 on a 100-point visual analog scale or as moderateor severe on a 4- or 5-point verbal response scale. The first dose ofanalgesia was administered when patients reported moderate to severepain in the postoperative setting. Studies that did not adequatelyrecord baseline pain severity or response to analgesia, were notrandomized or controlled or contained less than 45 patients wereexcluded from the meta-analysis. Tramadol, administered in a dosetitrated to pain response and via either IV (intravenous) or IM(intramuscular) intermittent injection, reduced pain intensity by 46.8%to 57.6% after 4 to 6 hours compared to 69.8% for morphine and 25.6% to51.3% for pentazocine. Efficacy of tramadol was maintained for theduration of the studies, which were ≤72 hours, and was comparable tomorphine or alfentanil. However, the onset of action of tramadol wasslower than morphine, as assessed by measurements approximately 3 hoursafter the first dose. There were no significant differences in thepercentage of patients treated with tramadol or morphine and who alsorequired rescue medication. The patient global response and physicianglobal response were similar for tramadol and for other opioids.

Tramadol injection (IV/IM/SC) is approved and used for the management ofmoderate to severe acute postoperative pain in several regions,including Europe, India and Australia/New Zealand (however, this dosageform is not available in the USA). Tramadol ampoules or vials for IV, IMand SC administration and preservative-free solutions for injection bythe various spinal routes (epidural, intrathecal, caudal, etc.) areavailable forms in these regions. Tramadol formulations approved inseveral countries include, tablets, capsules, effervescent powders, andsuppositories (Grond and Sablotzki, 2004; Rosenberg, 2009).

There is extensive data demonstrating that tramadol use is notassociated with the classical opioid side effects seen with more potentopioids. There are numerous reports of the safety and efficacy oftramadol (Lee et al., 1993; Scott and Perry, 2000; Grond and Sablotzki,2004). The most common adverse events of tramadol administration arenausea, dizziness, headache, somnolence, sweating, fatigue,constipation, dry mouth and vomiting. However, tramadol use,particularly with high doses, has been associated with seizures, and therisk of seizures is increased in the presence of drugs that reduceseizure threshold, head trauma or prior history of seizures.

Patients undergoing surgery, for example, total knee arthroplasty (TKA)and total hip arthroplasty (THA), typically demonstrate a need forshort-term analgesia, which is critical for earlier mobilization andrehabilitation. In this setting, assuring adequate pain relief withoutproviding extensive medical oversight required for some methods oftreatment (such as neuraxial anesthesia) and prevention of effects suchas opiate-induced respiratory depression and dependency would be highlybeneficial (Sinatra et al., 2002).

The goal of post-surgical pain management is twofold: i) to provide aquick onset of analgesic or pain relief and ii) to reduce or modulatethe quality and intensity of pain that a patient experiences in thepost-surgical period. While current treatments for management ofpost-surgical acute pain are useful, there is a need for improvedmethods for treating post-surgical acute pain.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide a method of treatingpain in human patients.

It is a further object of the present invention to provide a method oftreating pain in human patients who are unable to take oral medications,such as in a post-operative condition.

It is a further object of the present invention to provide a method oftreating pain in human patients that takes advantage of the faster onsetof intravenous administration of tramadol while providing additionalbenefits not available via current methodologies of tramadol intravenousadministration.

It is another object of the present invention to provide a method ofproviding a safe and effective alternative injectable analgesic for usein the acute postoperative setting.

It is another object of the present invention to provide a method fortreating pain in, e.g., the acute postoperative setting which is or maybe opioid-sparing.

It is another object of the present invention to provide a method fortreating pain with intravenous tramadol in human patients in a mannerthat may or does reduce side-effects (such as, e.g., nausea, vomiting orseizure).

It is a further object of the present invention to provide a method oftreating pain with a drug and dosing regimen that provides a positivebenefit-risk profile, and which addresses an unmet medical need for themanagement of acute postoperative pain.

In accordance with the above objects and others, the present inventionis directed in part to a method of administering tramadol for treatingpain via an intravenous dosing regimen comprising intravenouslyadministering a first dose of tramadol to a human patient in an amountfrom about 45 mg to about 80 mg; intravenously administering a seconddose of tramadol to the human patient in an amount from about 45 mg toabout 80 mg at a time from about 2 to about 3 hours after the firstdose; intravenously administering a third dose of tramadol to the humanpatient in an amount from about 45 mg to about 80 mg at a time fromabout 2 to about 3 hours after the second dose; and thereafterintravenously administering from about 45 mg to about 80 mg tramadol atdosage intervals from about 4 to about 6 hours, until the patient nolonger requires treatment with tramadol, such that the intravenousdosing regimen provides a Cmax and AUC of tramadol which is similar tothe Cmax and AUC of an oral dose of 100 mg tramadol HCl given every 6hours at steady-state. In certain preferred embodiments, each dose oftramadol is about 50 mg, or about 48 mg, or about 62 mg, or about 75 mg.In certain preferred embodiments, the dosing regimen further comprisesadministering additional doses of tramadol intravenously such that adaily dose from about 315 mg to about 560 mg tramadol is intravenouslyadministered over the first 24 hours of administration, and a daily dosefrom about 270 mg to about 480 mg tramadol is administered thereafter.

In certain preferred embodiments, each dose of tramadol is about 50 mg,the second dose is administered about 2 hours after the first dose, thethird dose is administered about 2 hours after the second dose, and thetramadol is dosed on an every 4 hour basis thereafter. In otherpreferred embodiments, each dose of tramadol is about 50 mg and isadministered every 4 hours after the second (or third dose) ofintravenous tramadol.

In certain other preferred embodiments, each dose of tramadol is about75 mg, the second dose is administered about 3 hours after the firstdose, the third dose is administered about 3 hours after the seconddose, and the tramadol is dosed on an every 6 hour basis thereafter.

In other preferred embodiments, each dose of tramadol is from about 45mg to about 55 mg, the second dose is administered about 2 hours afterthe first dose, the third dose is administered about 2 hours after thesecond dose, and the tramadol is dosed on an every 4 hour basisthereafter.

In other preferred embodiments, each dose of tramadol is from about 60mg to about 80 mg, the second dose is administered about from about 3 toabout 4 hours after the first dose, the third dose is administered about3 to about 4 hours after the second dose, and the tramadol is dosed onan every 6 hour basis thereafter.

The present invention is also directed in part to a method ofadministering tramadol for treating pain via an intravenous dosingregimen comprising intravenously administering a first dose of tramadolto a human patient in an amount of about 45 mg to about 55 mg;intravenously administering a second dose of tramadol to the humanpatient in an amount from about 45 mg to about 55 mg at about 2 hoursafter the first dose; intravenously administering a third dose oftramadol to the human patient in an amount from about 45 mg to about 55mg at about 2 hours after the second dose; and thereafter intravenouslyadministering from about 45 mg to about 55 mg tramadol at dosageintervals of about 4 hours, until the patient no longer requirestreatment with tramadol. In certain preferred embodiments, the doseadministered each time is about 50 mg. In certain preferred embodimentsof this method, the blood plasma levels of the parent compound (e.g.,Cmax and steady-state concentration) are almost reached at about 4 hoursafter the first intravenous dose of 50 mg tramadol. In certain preferredembodiments, the method comprises administering from about 315 mg toabout 385 mg tramadol intravenously over an initial 24 hour period oftreatment, and a daily dose from about 270 mg to about 330 mg dailythereafter.

The present invention is further directed to a method of administeringtramadol for treating pain via an intravenous dosing regimen comprisingintravenously administering a first dose of tramadol to a human patientin an amount of about 70 mg to about 80 mg; intravenously administeringa second dose of tramadol to the human patient in an amount from about70 mg to about 80 mg at about 3 hours after the first dose;intravenously administering a third dose of tramadol to the humanpatient in an amount from about 70 mg to about 80 mg at about 3 hoursafter the second dose; and thereafter intravenously administering fromabout 70 mg to about 80 mg tramadol at dosage intervals of about 6hours, until the patient no longer requires treatment with tramadol. Incertain preferred embodiments, the dose administered each time is about75 mg. In certain preferred embodiments of this method, the blood plasmalevels of the parent compound (e.g., Cmax) are reached at about 6 hoursafter the first intravenous dose of 75 mg tramadol. In further preferredembodiments, the method further comprises administering from about 350mg to about 400 mg tramadol intravenously over an initial 24 hour periodof treatment, and a daily dose from about 270 mg to about 330 mg dailythereafter.

In certain preferred embodiments, the intravenous dosing regimens of theinvention provide a Cmax and AUC of tramadol which is similar to theCmax and AUC of an oral dose of 100 mg tramadol HCl given every 6 hours,at steady-state.

In certain preferred embodiments, the intravenous dosing regimens of theinvention provide a Cmax of tramadol at steady-state that is from about80% to about 125% of the Cmax provided at steady-state by a 100 mg oraldose of tramadol HCl given every 6 hours.

In certain preferred embodiments, the intravenous dosing regimens of thepresent invention provide an AUC of tramadol at steady-state that isfrom about 80% to about 125% of the AUC provided at steady-state by a100 mg oral dose of tramadol HCl given every 6 hours.

In certain preferred embodiments, the intravenous dosing regimens of theinvention provide a Cmax of the M1 metabolite of tramadol atsteady-state that is from about 20% to about 125% (in certainembodiments from about 60% to about 75%), or from about 80% to about125% of the Cmax of the M1 metabolite of tramadol at steady-state whenthe tramadol is administered as oral 100 mg tramadol HCl every 6 hours.

In certain preferred embodiments, the intravenous dosing regimens of theinvention provide an AUC of the M1 metabolite of tramadol atsteady-state which is from about from about 20% to about 125% (incertain embodiments from about 60% to about 75%), or from about 80% toabout 125% of the steady-state AUC of the M1 metabolite of tramadol whenthe tramadol is administered as oral 100 mg tramadol HCl every 6 hours.

In certain embodiments of the intravenous dosing regimens of theinvention, the intravenous dosing regimen provides a Cmax of tramadol atsteady-state from about 80% to about 125% of about 676 ng/mL.

In certain embodiments of the intravenous dosing regimens of theinvention, the intravenous dosing regimen provides a Cmax and/or AUC ofthe M1 metabolite of tramadol at steady-state which is from about 20% toabout 125%, from about 60% to about 100%, or from about 80% to about125% of about 125 ng/mL.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the intravenous dosing regimen provides anAUC₂₄₋₄₈(h*ng/mL) of tramadol which is from about 80% to about 125% ofabout 11,020 hr*ng/mL, or about 11,020 hr*ng/mL±2852. In certainpreferred embodiments of the intravenous dosing regimens of theinvention, the intravenous dosing regimen provides an AUC₀₋₂₄(h*ng/mL)of tramadol which is from about 80% to about 125% of about 9520hr*ng/mL, or about 9520 hr*ng/mL±2106. In certain preferred embodimentsof the intravenous dosing regimens of the invention, the intravenousdosing regimen provides an AUC₀₋₄₈(h*ng/mL) of tramadol which is fromabout 80% to about 125% of about 20,540 hr*ng/mL, or about 20,540hr*ng/mL±4906.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the intravenous dosing regimen provides aAUC₂₄₋₄₈(h*ng/mL) of the M1 metabolite of tramadol which is from aboutfrom about 20% to about 125%, or from about 80% to about 125% of about2002 hr*ng/mL, or about 2002 hr*ng/mL±514.9. In certain preferredembodiments of the intravenous dosing regimens of the invention, theintravenous dosing regimen provides a AUC₀₋₂₄(h*ng/mL) of the M1metabolite of tramadol which is from about from about 20% to about 125%,or from about 80% to about 125% of about 1425 hr*ng/mL, or about 1425hr*ng/mL±405.4. In certain preferred embodiments of the intravenousdosing regimens of the invention, the intravenous dosing regimenprovides a AUC₀₋₄₈(h*ng/mL) of the M1 metabolite of tramadol which isfrom about from about 20% to about 125%, or from about 80% to about 125%of about 3427 hr*ng/mL, or about 3427 hr*ng/mL±889.9.

In preferred embodiments of the intravenous dosing regimens of theinvention, each dose of tramadol is administered intravenously over atime period from about 10 minutes to about 20 minutes. In certainpreferred embodiments, each dose of the tramadol is administered over atime interval of 15 (±2) minutes.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method further comprises administering a first doseof tramadol to the patient intra-operatively at wound closure, or fromfirst demand of analgesia post-operatively, and administering saidfurther doses of intravenous tramadol for at least two dayspost-surgery.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method further comprises administering one or moredoses of an intravenous opioid analgesic as rescue medicine to thepatient to treat breakthrough pain.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method further comprises administering the first doseof tramadol on first demand of analgesia post-operatively, furthercomprising administering a therapeutically effective dose intravenousopioid analgesic to the patient at the end of the surgery.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method further comprises administering the first doseof tramadol to the patient intra-operatively at wound closure, furthercomprising administering a bolus of a therapeutically effective dose ofintravenous opioid analgesic to the patient if the patient requestsanalgesia before the second dose of tramadol.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method further comprises administering a rescueopioid analgesic using Patient Controlled Analgesia (PCA).

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the treatment of pain in the patient is opioid-sparingover the first 48 hours post-surgery.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method further comprises diluting tramadol in avolume of normal saline to provide a unit dose from about 45 mg to about80 mg tramadol in said volume of normal saline; administering the doseof tramadol intravenously over a time period from about 15 (±2) minutes.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the dose prior to dilution is contained in one or moreampoules.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the ampoules contain tramadol hydrochloride and abuffering agent in water for injection.

In certain embodiments of the intravenous dosing regimens of theinvention, the human patient(s) is suffering from acute post-operativepain.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method provides a reduction in at least oneside-effect associated with tramadol therapy (e.g., as compared to priorart intravenous dosing regimens), wherein the side-effect is nausea,vomiting, or seizure.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method further comprises administering atherapeutically effective dose of an intravenous opioid analgesic isadministered to the patient (i) at the end of the surgery, (ii) if thepatient requests analgesia before the second dose of tramadol, or (iii)both (i) and (ii).

In certain preferred embodiments, the present invention is directed inpart to a method of treating pain, comprising administering to a humanpatient(s) a therapeutically effective dose of tramadol intravenouslyover a time period from about 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20 21, 22, 23, 24, 25, 26, 27, 28, 29 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44 or 45 minutes.

Further aspects of the invention are directed to diluting the dose oftramadol in from about 50 ml to about 500 ml (and preferably from about50 ml to about 100 ml) of a pharmaceutically acceptable fluid forinjection such as normal saline, e.g., in a bag, and standardizing theadministration of the injection of the dose of tramadol via the use of apump.

In another preferred embodiment, the dose of tramadol is provided in theform of a sterile solution at a concentration of about 50 mg tramadolhydrochloride/1 ml prior to dilution.

In certain further preferred embodiments, the dose of tramadol prior todilution is contained in one or more ampoules. In certain preferredembodiments, the ampoules contain the dose of tramadol (e.g., tramadolhydrochloride) together with a buffering agent (e.g., sodium acetate) inwater for injection (e.g., about 1 ml to about 5 ml).

In certain further preferred embodiments, the method further comprisesdiluting the dose of tramadol into an IV bag for administration to thepatient.

In certain preferred embodiments of the present invention, the methodfurther comprises administering a first dose of tramadol to the patientintra-operatively at wound closure, or from first demand of analgesiapostoperatively, and administering said further doses of intravenoustramadol for at least two days post-surgery.

In certain preferred embodiments of the present invention, the methodfurther comprises the concomitant administration of one or more opioidanalgesics, preferably via the injectable (e.g., intravenous) route asrescue medicine to the patient to treat breakthrough pain that thepatient experiences, e.g., for the time period of at least about 48hours post-surgery. Several options are available for postoperative painmanagement (Singelyn et al., 1998; Sinatra et al., 2002; both of whichare hereby incorporated by reference). Options include intermittent“on-demand” analgesia, continuous epidural analgesia with opioids and/orlocal anesthetics is effective, or to provide a combination of nerveblocks with long-acting local anesthetics and/or opioids initiatedintra-operatively and continued into the immediate postoperative period.For example, most Total knee Arthroplasty (TKA) or Total HipArthroplasty (THA) procedures are currently performed with regional (orneuraxial) or other nerve blocks and without general anesthesia. Incertain preferred embodiments of the invention, the method furthercomprises administering a rescue opioid analgesic using PatientControlled Analgesia (PCA). In certain preferred embodiments, theintravenous administration of opioid analgesic also or alternativelycomprises opioid analgesic (e.g., morphine) intravenously to the patientat an effective dose (e.g., morphine in an amount of about 0.05 mg/kg)as a bolus at the end of surgery or upon first demand of analgesiapostoperatively, to provide effective analgesia to the patient(s).

In certain preferred embodiments of the invention, the first dose oftramadol is administered on first demand of analgesia postoperatively.Thereafter, the method may further comprise administering atherapeutically (analgesically) effective dose intravenous opioidanalgesic to the patient at the end of the surgery, to provide effectiveanalgesia to the patient(s).

In certain preferred embodiments of the invention, the first dose oftramadol is administered to the patient intra-operatively at woundclosure. In such embodiments, the method may further compriseadministering a bolus of a therapeutically (analgesically) effectivedose of intravenous opioid analgesic to the patient if the patientrequests analgesia before the second dose of tramadol, to provideeffective analgesia to the patient(s).

In preferred embodiments where the tramadol is administered for thetreatment of post-operative pain, the treatment of pain in the patientis opioid-sparing over the first 48 hours post-surgery.

In other preferred embodiments, the human patient(s) suffering from painis unable to ingest an oral dosage form (e.g., of tramadol or anotheropioid analgesic and/or an NSAID) because the patient is suffering fromcancer pain.

In accordance with the above, the final drug product (containing theintravenous dose of tramadol) may be presented as, e.g., as unit-doseampoules, unit-dose vials, multi-dose ampoules, multi-dose vials, anddrug in pre-mixed bags.

In certain preferred embodiments, the M1 metabolite of tramadol(O-desmethyltramadol) contributes to analgesic effect provided by thepresent invention (dosing regimen), without being toxic (e.g., withoutsignificant side effects) to humans at the administered dose ofintravenous tramadol.

The present invention is also directed in part to a method ofadministering tramadol for treating pain via an intravenous dosingregimen comprising intravenously administering at least one loading doseof tramadol to a human patient; thereafter intravenously administeringat least one dose of tramadol to the human patient at a dosing intervalfrom about 2 to about 3 hours after administration of the loading dose,and thereafter intravenously administering doses of tramadol at a dosinginterval of about 4 to about 6 hours until the patient no longerrequires treatment with tramadol, wherein each dose of tramadol is in anamount from about 45 mg to about 80 mg. In certain embodiments, the Cmaxof each dose of the intravenous tramadol dosing regimen is from about80% to about 125% of about 676 ng/mL and the AUC₆ of the intravenoustramadol is from about 80% to about 125% of 3230 hr*ng/mL. In certainembodiments, each trough plasma level provided during the tramadoldosing regimen is about the same or greater than the trough levelprovided by a 100 mg oral dose of tramadol HCl given every 6 hours, atsteady-state. In further embodiments, the Cmax of the M1 metabolite oftramadol in the intravenous dosing regimen at steady-state is from about20% to about 125% or from about 80% to about 125% of about 125 ng/mL.

The invention is further directed in part to a method of improving thesafety and tolerability of tramadol for treating pain in human patients,comprising intravenously administering intravenously administering fromabout 45 mg to about 80 mg tramadol at dosage intervals from about 4 toabout 6 hours, except for an additional loading dose administered fromabout 2 to about 3 hours after the first intravenous dose of tramadol,such that the intravenous dosing regimen provides a steady-state Cmaxand AUC of tramadol at about 4 to about 6 hours after initiation ofintravenous tramadol therapy, which is similar to the steady-state Cmaxand AUC of oral doses of 100 mg tramadol HCl given every 6 hours. Incertain embodiments, the method may provide a faster onset of painrelief than oral doses of 100 mg tramadol HCl given every 6 hours.

The invention is further directed in part to a method of improving thesafety and tolerability of tramadol for treating pain in human patients,comprising intravenously administering a first dose of tramadol to ahuman patient in an amount from about 45 mg to about 80 mg;intravenously administering a second dose of tramadol to the humanpatient in an amount from about 45 mg to about 80 mg at a time fromabout 2 to about 3 hours after the first dose; intravenouslyadministering a third dose of tramadol to the human patient in an amountfrom about 45 mg to about 80 mg at a time from about 2 to about 3 hoursafter the second dose; and thereafter intravenously administering fromabout 45 mg to about 80 mg tramadol at dosage intervals from about 4 toabout 6 hours, until the patient no longer requires treatment withtramadol, such that the intravenous dosing regimen provides asteady-state Cmax and AUC of tramadol at about 4 to about 6 hours afterinitiation of intravenous tramadol therapy which is similar to thesteady-state Cmax and AUC of oral doses of 100 mg tramadol HCl givenevery 6 hours.

The invention is further directed in part to a method of administeringtramadol for treating pain via an intravenous dosing regimen comprisingintravenously administering a first dose of tramadol to a human patientin an amount of about 50 mg; intravenously administering a second doseof tramadol to the human patient in an amount of about 50 mg at about 2hours after the first dose; intravenously administering a third dose oftramadol to the human patient in an amount of about 50 mg at about 2hours after the second dose; and thereafter intravenously administeringadditional doses of tramadol to the human patient in an amount of about50 mg tramadol at dosage intervals of about 4 hours, until the patientno longer requires treatment with tramadol, wherein the tramadol istramadol base or a pharmaceutically acceptable salt of tramadol.Preferably, the intravenous dosing regimen of this embodiment provides aCmax and AUC of tramadol which is similar to the Cmax and AUC of an oraldose of 100 mg tramadol HCl given every 6 hours, at steady-state.Preferably, the intravenous dosing regimen provides a mean Cmax oftramadol at steady-state from about 80% to about 125% of about 736ng/mL, or a mean Cmax of tramadol at steady-state of about 736ng/mL±152. Preferably, the intravenous dosing regimen provides a meansteady-state concentration of the M1 metabolite of tramadol atsteady-state which is from about 20% to about 125% or from about 60% toabout 125% of the mean steady-state concentration of the M1 metaboliteof tramadol provided by a dosing regimen of 100 mg tramadol HCladministered orally every 6 hours, at steady-state; or from about 80% toabout 125% of about 128 ng/mL, or a mean steady-state concentration ofthe M1 metabolite of tramadol of about 88.9 ng/mL±22.3. Preferably, themean tramadol Cmax for the first dose of tramadol is from 80% to about125% of about 294 ng/ml or about 294 ng/mL±68.5. In this embodiment, themean tramadol concentration for the intravenous dosing regimen providessimilar steady-state peak and trough concentrations as compared to adosing regimen of 100 mg tramadol HCl administered orally every 6 hours,at steady-state. Preferably, the mean tramadol concentration for theintravenous dosing regimen at 48 hours after the first administered doseof tramadol is about 448 ng/ml±131. Preferably, the P/T ratio oftramadol at 48 hours after the first administered dose of tramadol isabout 1.6370±0.2655, and the P/T ratio of tramadol after the firstadministered dose of tramadol is about 1.4566±0.2812. Preferably, themean Cmax₂₋₄ (ng/ml) is about 479±77.7. Preferably, the mean Cmaxconcentration after administration of the third administered dose oftramadol is similar to the mean Cmax at steady-state, which in turn issimilar to the Cmax at steady-state for a dosing regimen of 100 mgtramadol HCl administered orally every 6 hours. In certain preferredembodiments, the tramadol concentration at steady-state for this 50 mgdosing regimen is about 557 ng/mL±131. In certain preferred embodiments,the tramadol M1 metabolite concentration at steady-state for this 50 mgdosing regimen is about 88.9 ng/mL±22.3. In certain preferredembodiments, the human patient(s) is suffering from acute post-operativepain. In further embodiments, the method may result in a reduction in atleast one side-effect associated with tramadol therapy, wherein theside-effect is nausea, vomiting, or seizure. In certain preferredembodiments, a therapeutically effective dose of an intravenous opioidanalgesic is administered to the patient (i) at the end of the surgery,(ii) if the patient requests analgesia before the second dose oftramadol, or (iii) both (i) and (ii). In certain preferred embodiments,each dose of tramadol is administered intravenously over a time periodfrom about 10 minutes to about 20 minutes, or each dose of tramadol isadministered over a time interval of 15 (±2) minutes. In certainpreferred embodiments, the pharmacokinetic profile (e.g., plasmaconcentration curve of tramadol and/or the M1 metabolite of tramadol)achieved with this 50 mg dosing regimen provides surprisingly reducedfluctuation (e.g., peak to trough variance) as compared to a higher(e.g., 75 mg or 100 mg) intravenous dosing regimen. In certain preferredembodiments, the pharmacokinetic profile (e.g., Cmax and AUC) achievedby this 50 mg IV tramadol dosing regimen at a time where the patientmight be switched to oral meds (e.g., after the 44-48 hour dosinginterval) is similar to the pharmacokinetic profile (e.g., Cmax and AUC)provided at steady-state by a dosing regimen of 100 mg tramadol HCladministered orally every 6 hours. This allows the patient to be steppeddown from the intravenous tramadol dosing regimen to an oral dosingregimen. In turn, this allows the patient to be discharged from hospitalcare with less concern about deleterious effects which might occur froma switch from intravenous to oral analgesic medicine (e.g., the switchto an oral version of the drug providing a much different Cmax and AUC).

In another embodiment of the invention, an IV tramadol dosing regimen is75 mg administered at Hour 0, followed by 75 mg at Hour 3 and Hour 6,and 75 mg every 6 hours thereafter (e.g., until the patient no longerrequires treatment). Thus, in this embodiment, the invention is directedto a method of administering tramadol for treating pain via anintravenous dosing regimen comprising intravenously administering afirst dose of tramadol to a human patient in an amount of about 75 mg;intravenously administering a second dose of tramadol to the humanpatient in an amount of about 75 mg at about 3 hours after the firstdose; intravenously administering a third dose of tramadol to the humanpatient in an amount of about 75 mg at about 6 hours after the seconddose; and thereafter intravenously administering additional doses oftramadol to the human patient in an amount of about 75 mg tramadol atdosage intervals of about 6 hours, until the patient no longer requirestreatment with tramadol, wherein the tramadol is tramadol base or apharmaceutically acceptable salt of tramadol. In certain embodiments,this 75 mg intravenous dosing regimen provides a Cmax of tramadol atsteady-state from about 80% to about 125% of about 827 ng/mL, or 827ng/mL±234; or from about 80% to about 125% of about 932 ng/mL, or about932 ng/mL±199. In certain embodiments, this 75 mg intravenous dosingregimen provides a mean steady-state concentration of the M1 metaboliteof tramadol at steady-state which is from about 20% to about 125%, orfrom about 60% to about 125%; or from about 80% to about 125% of about86.6 ng/mL, or about 86.6 ng/mL±23.8. In certain embodiments, this 75 mgdosing regimen provides a mean tramadol Cmax for the first dose oftramadol from 80% to about 125% of about 484 ng/ml, or 484 ng/mL±155. Incertain preferred embodiments for this 75 mg dosing regimen, the meantramadol concentration for the intravenous dosing regimen providessimilar steady-state peak and trough concentrations as compared to adosing regimen of 100 mg tramadol HCl administered orally every 6 hours,at steady-state. In certain preferred embodiments for this 75 mg dosingregimen, the mean tramadol concentration for the intravenous dosingregimen at 48 hours after the first administered dose of tramadol isfrom about 80% to about 125% of about 354 ng/mL, or about 354ng/mL±85.9. In certain preferred embodiments for this 75 mg dosingregimen, the P/T ratio of tramadol after the first administered dose oftramadol is about 2.0658±0.6131. In certain preferred embodiments forthis 75 mg dosing regimen, the P/T ratio of tramadol after the doseadministered at 45 hours after the first administered dose of tramadolis about 2.3692±0.5090. In certain preferred embodiments for this 75 mgdosing regimen, the mean Cmax₃₋₆ is from about 80% to about 125% of 756ng/mL, or about 756 ng/mL±141. In certain embodiments for this 75 mgdosing regimen, the human patient(s) is suffering from acutepost-operative pain. In certain preferred embodiments for this 75 mgdosing regimen, a reduction in at least one side-effect associated withtramadol therapy may be achieved, wherein the side-effect is nausea,vomiting, or seizure. In certain preferred embodiments for this 75 mgdosing regimen, a therapeutically effective dose of an intravenousopioid analgesic is administered to the patient (i) at the end of thesurgery, (ii) if the patient requests analgesia before the second doseof tramadol, or (iii) both (i) and (ii). In certain preferredembodiments for this 75 mg dosing regimen, each dose of tramadol isadministered intravenously over a time period from about 10 minutes toabout 20 minutes, or over a time interval of 15 (±2) minutes. In certainpreferred embodiments, the pharmacokinetic profile (e.g., Cmax and AUC)achieved by this 75 mg IV tramadol dosing regimen at a time where thepatient might be switched to oral meds (e.g., after the 42-48 hourdosing interval) is similar to the pharmacokinetic profile (e.g., Cmaxand AUC) provided at steady-state by a dosing regimen of 100 mg tramadolHCl administered orally every 6 hours. This allows the patient to bestepped down from the intravenous tramadol dosing regimen to an oraldosing regimen. In turn, this allows the patient to be discharged fromhospital care with less concern about deleterious effects which mightoccur from a switch from intravenous to oral analgesic medicine (e.g.,the switch to an oral version of the drug providing a much differentCmax and AUC).

In certain embodiments, the invention is directed to a method ofadministering tramadol for treating pain in a human patient(s) via anintravenous dosing regimen, comprising intravenously administering afirst dose of tramadol to a human patient(s) in an amount of about 50mg; intravenously administering a second dose of tramadol to the humanpatient(s) in an amount of about 50 mg at about 2 hours after the firstdose; and intravenously administering a third dose of tramadol to thehuman patient(s) in an amount of about 50 mg at about 2 hours after thesecond dose; and thereafter intravenously administering additional dosesof tramadol to the human patient(s) in an amount of about 50 mg tramadolat dosage intervals of about 4 hours, such that such that the mean Cmaxafter the first dose is about 273±60 ng/mL, the mean Cmax after thesecond dose is about 451±65 ng/mL, and the mean Cmax concentration afteradministration of the third administered dose of tramadol is about 666ng/mL±135, wherein the tramadol is tramadol base or a pharmaceuticallyacceptable salt of tramadol. In certain preferred embodiments, the meanCmax at steady-state obtained in this embodiment is about 736 ng/mL±152;and/or the mean Cmax obtained in this embodiment is similar to thesteady-state Cmax of about 701 ng/mL±178 obtained by a dosing regimen of100 mg tramadol HCl administered orally every 6 hours; and/or such thatthe mean Cmax and AUC (e.g., AUC₀₋₄₈) is similar to the steady-stateCmax and AUC₀₋₄₈ of an oral dose of 100 mg tramadol HCl given every 6hours; and/or such that the intravenous dosing regimen provides asteady-state Cmax of about 736±152 ng/ml and a Css of about 557±131ng/ml; and/or such that the intravenous dosing regimen provides anaverage steady state concentration (Css) of about 557 ng/mL±131 ng/mland that exposure to tramadol at steady-state, based on Cmax andAUC₀₋₄₈, is similar to the Cmax and AUC₀₋₄₈ of an oral dose of 100 mgtramadol HCl given every 6 hours. Certain embodiments further comprisecontinuing to administer additional doses of tramadol to the humanpatient in an amount of about 50 mg tramadol at dosage intervals ofabout 4 hours for at least about 44 hours after the first administereddose of tramadol; and/or comprising continuing to administer additionaldoses of tramadol to the human patient in an amount of about 50 mgtramadol at dosage intervals of about 4 hours for at least about 44hours after the first administered dose of tramadol, such that theintravenous dosing regimen provides a Cmax of tramadol at steady-stateof about 736 ng/mL±152; and/or continuing to administer additional dosesof tramadol to the human patient in an amount of about 50 mg tramadol atdosage intervals of about 4 hours for at least about 24 hours after thefirst administered dose of tramadol, such that the intravenous dosingregimen provides an AUC₀₋₂₄ of about 9520 h*ng/ml±2106; and/orcontinuing to administer additional doses of tramadol to the humanpatient in an amount of about 50 mg tramadol at dosage intervals ofabout 4 hours for at least about 44 hours after the first administereddose of tramadol, such that the intravenous dosing regimen provides anAUC₀₋₄₈ of about 20,540 h*ng/ml±4906.

The term “about 50 mg” should be construed with the goal of the presentinvention in mind—the dose of the dose (“about”) may be adjusted to alimited degree, e.g., as long as the goal of a mean Cmax and preferablyAUC (e.g., an AUC at AUC₀₋₄₈) which is similar to the mean steady-stateCmax and AUC (e.g., an AUC at AUC₀₋₄₈) that is obtained via theadministration of an oral dosing regimen of 100 mg tramadol administeredto human patients every 6 hours (if the dosing regimen is continued for48 hours). To the extent that an AUC limitation appears in the claims,it should be interpreted to mean that if continued for a 48 hour timeperiod, the AUC₀₋₄₈ of the claimed intravenous 50 mg tramadol dosingregimen will be similar to the AUC₀₋₄₈ obtained via the oral 100 mgtramadol Q6H dosing regimen. Likewise, the terms “about 2 hours” and“about 4 hours” with respect to the time intervals between intravenoustramadol doses as set forth herein should be construed with the goal ofthe present invention in mind—the timing of the dose (“about”) may beadjusted to a limited degree, e.g., as long as the goal of a mean Cmaxand AUC (e.g., an AUC at AUC₀₋₄₈) which is similar to the meansteady-state Cmax and AUC (e.g., an AUC at AUC₀₋₄₈) that is obtained viathe administration of an oral dosing regimen of 100 mg tramadoladministered to human patients every 6 hours (if the dosing regimen iscontinued for 48 hours). Generally speaking, it should be recognizedthat the a dose(s) of the drug (intravenous tramadol) may be modified,e.g., to a dose from about 45 mg to about 55 mg and a dosing intervalfor the second dose of intravenous tramadol may be modified to a timefrom about 1.5 to about 2.5 hours after the first dose, and a dosinginterval for the third dose of intravenous tramadol may be modified to atime from about 1.5 to about 2.5 hours after the second dose, and/or thedosing interval for the one or more intravenous tramadol dosesadministered after the third intravenous tramadol dose may beadministered from about 3.5 to about 4.5 hours after the previous dose,e.g., as long as the goal of a mean Cmax and AUC (e.g., an AUC atAUC₀₋₄₈) which is similar to the mean steady-state Cmax and preferablyAUC (e.g., an AUC at AUC₀₋₄₈) that is obtained via the administration ofan oral dosing regimen of 100 mg tramadol administered to human patientsevery 6 hours (if the dosing regimen is continued for 48 hours).

The invention is further directed to a method of administering tramadolfor treating pain in a human patient(s) via an intravenous dosingregimen, comprising intravenously administering a first dose of tramadolto a human patient(s) in an amount from about 45 mg to about 55 mg;intravenously administering a second dose of tramadol to the humanpatient(s) in an amount from about 45 mg to about 55 mg at about 1.5 toabout 2.5 hours after the first dose; intravenously administering athird dose of tramadol to the human patient(s) in an amount from about45 mg to about 55 mg at about 1.5 to about 2.5 hours after the seconddose; and thereafter intravenously administering additional doses oftramadol to the human patient(s) in an amount from about 45 mg to about55 mg tramadol at dosage intervals of about 3.5 to about 4.5 hours, suchthat exposure to tramadol at steady-state, based on Cmax and AUC (e.g.,AUC₀₋₄₈), is similar to the Cmax and AUC₀₋₄₈ of an oral dose of 100 mgtramadol HCl given every 6 hours, wherein the tramadol is tramadol baseor a pharmaceutically acceptable salt of tramadol. In certain preferredembodiments, the mean Cmax at steady-state obtained in this embodimentis about 736 ng/mL±152; and/or the mean Cmax obtained in this embodimentis similar to the steady-state Cmax of about 701 ng/mL±178 obtained by adosing regimen of 100 mg tramadol HCl administered orally every 6 hours;and/or such that the mean Cmax and AUC (e.g., AUC₀₋₄₈) is similar to thesteady-state Cmax and AUC₀₋₄₈ of an oral dose of 100 mg tramadol HClgiven every 6 hours; and/or such that the intravenous dosing regimenprovides a steady-state Cmax of about 736±152 ng/ml and a Css of about557±131 ng/ml; and/or such that the intravenous dosing regimen providesan average steady state concentration (Css) of about 557 ng/mL±131 ng/mland that exposure to tramadol at steady-state, based on Cmax andAUC₀₋₄₈, is similar to the Cmax and AUC₀₋₄₈ of an oral dose of 100 mgtramadol HCl given every 6 hours. Certain embodiments further comprisecontinuing to administer additional doses of tramadol to the humanpatient in an amount of about 50 mg tramadol at dosage intervals ofabout 4 hours for at least about 44 hours after the first administereddose of tramadol; and/or comprising continuing to administer additionaldoses of tramadol to the human patient in an amount of about 50 mgtramadol at dosage intervals of about 4 hours for at least about 44hours after the first administered dose of tramadol, such that theintravenous dosing regimen provides a Cmax of tramadol at steady-stateof about 736 ng/mL±152; and/or continuing to administer additional dosesof tramadol to the human patient in an amount of about 50 mg tramadol atdosage intervals of about 4 hours for at least about 24 hours after thefirst administered dose of tramadol, such that the intravenous dosingregimen provides an AUC₀₋₂₄ of about 9520 h*ng/ml±2106; and/orcontinuing to administer additional doses of tramadol to the humanpatient in an amount of about 50 mg tramadol at dosage intervals ofabout 4 hours for at least about 44 hours after the first administereddose of tramadol, such that the intravenous dosing regimen provides anAUC₀₋₄₈ of about 20,540 h*ng/ml±4906. In certain preferred embodiments,the mean Cmax after the first dose is about 273±60 ng/mL, and/or themean Cmax after the second dose is about 451±65 ng/mL, and/or and themean Cmax concentration after administration of the third administereddose of tramadol is about 666 ng/mL±135.

The methods of the present invention are described in further detail inthe following sections. However, it should be understood that forpurposes of the present invention, the following terms have thefollowing meanings:

The term “acute pain” as used herein means pain that has a sudden onsetand commonly declines over a short time (days, hours, minutes) andfollows injury to the body and which generally disappears when thebodily injury heals.

The term “effective analgesia” is defined for purposes of the presentinvention as a satisfactory reduction in or elimination of pain, alongwith the process of a tolerable level of side effects, as determined bythe human patient.

The term “effective pain management” means for purposes of the presentinvention as the objective evaluation of a human patient's response(pain expressed versus side effects) to analgesic treatment by aphysician as well as subjective evaluation of therapeutic treatment bythe patient undergoing such treatment. The skilled artisan willunderstand that effective analgesia will vary according to many factors,including individual patient variations.

The term “breakthrough pain” means pain which the patient experiencesdespite the fact that the patient is being administered generallyeffective amounts of, e.g., an opioid analgesic such as buprenorphine.

The term “rescue” refers to a dose of an analgesic which is administeredto a patient experiencing breakthrough pain.

An “effective amount” is an amount sufficient to effect beneficial ordesired clinical results including alleviation or reduction in pain. Insome embodiments, the “effective amount” may reduce the pain of ongoingpain and/or breakthrough pain (including ambulatory pain andtouch-evoked pain).

The term “parenterally” as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection or infusiontechniques.

The term “patient” as used herein refers to a warm blooded animal suchas a mammal which is the subject of trauma, e.g., surgical trauma. It isunderstood that at least humans, dogs, cats, and mice are within thescope of the meaning of the term.

As used herein, the term “treat” or “treatment”, or a derivativethereof, contemplates partial or complete inhibition of acute pain, whena composition of the present invention is administered following theonset of acute pain.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of the modeled geometric mean oftramadol concentrations at steady-state when administered Q6h and Q4hfor Example 1.

FIG. 2 is a graphical representation of the modeled plasma curve ofExample 3a (100 mg loading dose) plotted against the plasma curveprovided by a 100 mg oral tramadol dose given every 6 hours.

FIG. 3 is a graphical representation of the modeled plasma curve ofExample 3b (50 mg loading at 2 hr) plotted against the plasma curveprovided by a 100 mg oral tramadol dose given every 6 hours.

FIG. 4 is a graphical representation of the simulated tramadol plasmalevels of Example 4 plotted against the plasma concentration curves fora 100 mg and a 50 mg oral tramadol dose administered every 6 hours, atsteady-state.

FIG. 5 is a graphical representation of the simulated M1 metaboliteplasma levels of Example 4 plotted against the M1 metabolite plasmaconcentration curves for a 100 mg and a 50 mg oral tramadol doseadministered every 6 hours, at steady-state.

FIG. 6 is a graphical representation of the simulated plasmaconcentration of Example 4 over the initial 24 hours.

FIG. 7 is a graphical representation of the simulated M1 metaboliteplasma concentration of Example 4 over the initial 24 hours.

FIG. 8 is a graphical representation of the simulated tramadol plasmaconcentration of Example 4 over the initial 24 hours, plotted againstthe tramadol plasma concentration of the 100 mg oral tramadoladministered every 6 hours, and the reference plasma concentration of676 ng/ml.

FIG. 9 provides the mean plasma tramadol time-concentration profiles forthe 100 mg oral, 50 mg IV, and 75 mg IV regimens of the study conductedin Example 5.

FIG. 10 provides the mean plasma O-desmethyltramadol time-concentrationprofiles for the 100 mg oral, 50 mg IV, and 75 mg IV regimens of thestudy conducted in Example 5.

FIG. 11 provides the observed mean (STD) tramadol plasma concentrationversus time curve for IV 50 mg and oral 100 mg as well as the fittedcurve for the oral 100 mg for the initial 12 hours after administrationfor the study conducted in Example 5.

FIG. 12 is a graph illustrating that for Example 5, the 50 mg IV regimenis very close to steady-state after the 3rd dose, due to the loadingdose strategy (comparable Cmax after the hour 4 dose to Cmax after theHour 44 dose), and that the oral Cmax is achieved later but reaches asimilar level to the 50 mg IV regimen.

DETAILED DESCRIPTION

The chemical name for tramadol is(±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanolhydrochloride [or(1R,2R)-rel-2-[(dimethyl-amino)methyl]-1-(3-methoxyphenyl) cyclohexanolhydrochloride, (1RS, 2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol hydrochloride, (±)-(RR,SS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanolhydrochloride]. Unless otherwise specified, the term tramadol refers tothe racemic mixture of the (±)cis isomers.

Tramadol is a centrally-acting synthetic analgesic of theaminocyclohexanol group with opioid-like effects. Tramadol isextensively metabolized following administration resulting in a numberof enantiomeric metabolites which display different opioid-receptorbinding properties, and monoaminergic reuptake inhibition (Grond andSablotzki, 2004). Both enantiomers of tramadol and (+)-M are responsiblefor the analgesic effect. The primary metabolite [(+)-M or(+)-O-desmethyltramadol] of tramadol confers significant μ-opioidactivity; (+)-tramadol confers weak μ-opioid activity and significantserotonin reuptake inhibition; and (−)-tramadol is responsible for theinhibition of noradrenaline re-uptake (Gillen et al., 2000; Raffa,2008). Nonclinical studies have shown that antinociception induced bytramadol is only partially antagonized by the opiate antagonist,naloxone, indicating that non-opioid mechanisms are also involved in itspharmacodynamic action (Collart et al., 1992).

Tramadol has efficacy in management of acute postoperative painequivalent to morphine and other opioids administered intravenously,although the onset of action for tramadol is slower. The parenteralroute has the advantage of immediate bioavailability and faster onset ofaction than oral, and is available to postoperative patients who cannottake oral medications. Current standard-of-care injectable analgesics(opioids and NSAIDs) have significant adverse effects, includingopiate-induced respiratory depression, excessive sedation, hypotension,dependency, increased bleeding risk, renal toxicity and gastrointestinalirritation, which can potentially slow the postoperative rehabilitationprocess and compound the risk inherent in any surgical procedure.

Tramadol is currently commercially available in variouscountries/territories in the following forms: 50 mg/ml or 100 mg/2 ml,solution for injection; 50 mg, capsules, hard; 50 mg, prolonged-releasetablets; 100 mg, prolonged-release tablets; 150 mg, prolonged-releasetablets; 200 mg, prolonged-release tablets; 50 mg, tablets; 100 mg/ml,oral drops, solution; and 100 mg, suppositories. In the U.S., tramadolis approved by the Food and Drug Administration (FDA) and marketed as anoral capsule/tablet for moderate to moderately severe pain in adults,e.g., under the tradename Ultram® (tramadol hydrochloride tablets).

Parenteral tramadol has been used extensively in Europe and other areasof the world for the amelioration of postoperative pain in both adultsand children. The efficacy of tramadol has been thoroughly reviewed (LeeC R, McTavish D, Sorkin E M. Tramadol. A preliminary review of itspharmacodynamic and pharmacokinetic properties, and therapeuticpotential in acute and chronic pain states. Drugs. 1993; 46:313-340;Scott L J, Perry C M. Tramadol. A review of its use in perioperativepain. Drugs. 2000; 60:139-176; Grond S and Slabotzi A. Clinicalpharmacology of tramadol. Clin Pharmacokinet. 2004; 43:879-923).Parenteral tramadol in such territories consists of tramadol 50 mg or100 mg administered as a slow bolus injection (over 2-3 minutes) every4-6 hours.

Surgical procedures often result in some form of acute pain. Surgicalpain may include nociceptive, neuropathic or psychological components.Nociceptive pain is a pain experienced as a result of nociception, whichis detection of a stimulus by a pain receptor (nociceptor) andtransmission of the information to the brain along nerves. Nociceptivepain is caused by tissue damage and inflammation in response to trauma.The resulting pain is usually not well localized and is opioidresponsive.

Several options are available for postoperative pain management(Singelyn et al., 1998; Sinatra et al., 2002). Options includeintermittent “on-demand” analgesia, continuous epidural analgesia withopioids and/or local anesthetics is effective, or to provide acombination of nerve blocks with long-acting local anesthetics and/oropioids initiated intra-operatively and continued into the immediatepostoperative period. In the United States (US) and in India, thislatter strategy is frequently employed, and most TKA and THA proceduresare currently performed with regional (or neuraxial) or other nerveblocks and without general anesthesia. Each of these options forpostoperative pain management can be used concomitantly with theintravenous tramadol treatments described herein as recue medicine totreat breakthrough pain.

The present invention is directed in part to tramadol in apharmaceutically acceptable sterile solution formulation containing aneffective dose of tramadol or a pharmaceutically acceptable saltthereof, and a method of administration of the same for the treatment ofpain, e.g., postoperatively. Tramadol injection in accordance with thepresent invention will fulfill an important need by providing a safe andeffective alternative injectable analgesic for use in the acutepostoperative setting.

Preferably, the dose of tramadol administered in accordance with thepresent invention is, e.g., from about 45 mg to about 80 mg, and incertain preferred embodiments from about 45 to about 55 mg, or fromabout 70 to about 80 mg, or from about 55 to about 65 mg. In certainpreferred embodiments, each tramadol dose administered is in the amountof, e.g., 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59,60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77,78, 79 or 80 mg, e.g., provided as tramadol hydrochloride. The tramadolmay be provided, e.g., as 50 mg tramadol hydrochloride/1 ml. Theinjectable tramadol dose is generally intended for in-hospital use,although it can be used in other settings. In certain preferredembodiments, the tramadol is administered intravenously over a timeperiod from about 10 minutes to about 3 hours. In certain preferredembodiments, the therapeutically effective dose of tramadolintravenously over a time period from about 10 minutes to about 20minutes, and most preferably in certain embodiments about 15 (±2)minutes. Thus, in preferred embodiments, the therapeutically effectivedose of tramadol intravenously over a time period from about 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, or 20 minutes.

Further aspects of the invention are directed to diluting the dose oftramadol in from about 50 ml to about 100 ml of a pharmaceuticallyacceptable fluid for injection (such as normal saline), andstandardizing the administration of the injection of the dose oftramadol via the use of a pump. In preferred embodiments, the pump is aninfusion pump that is commercially available, such as pumps availablefrom Braun and Hospira.

As previously mentioned, the dose of tramadol administered in accordancewith the present invention may be diluted in a suitable pharmaceuticallyacceptable carrier for injection. Examples of such include sterile waterfor injection, normal saline, etc. Intravenous fluids are well known tothose of ordinary skill in the art, and may include other ingredientsbeyond the dose of tramadol and the carrier/solvent for the tramadol,e.g., sterile solutions of simple chemicals such as sugars, amino acidsor electrolytes, which can be easily carried by the circulatory systemand assimilated. Such fluids are typically prepared with water forinjection USP. Fluids used commonly for intravenous (IV) use aredisclosed in Remington, The Science and Practice of Pharmacy [fullcitation previously provided], and include: alcohol, e.g., 5% alcohol(e.g., in dextrose and water (“D/W”) or D/W in normal saline solution(“NSS”), including in 5% dextrose and water (“D5/W”), or D5/W in NSS);synthetic amino acid such as Aminosyn, FreAmine, Travasol, e.g., 3.5 or7; 8.5; 3.5, 5.5 or 8.5% respectively; ammonium chloride e.g., 2.14%;dextran 40, in NSS e.g., 10% or in D5/W e.g., 10%; dextran 70, in NSSe.g., 6% or in D5/W e.g., 6%; dextrose (glucose, D5/W) e.g., 2.5-50%;dextrose and sodium chloride e.g., 5-20% dextrose and 0.22-0.9% NaCl;lactated Ringer's (Hartmann's) e.g., NaCl 0.6%, KCl 0.03%, CaCl₂ 0.02%;lactate 0.3%; mannitol e.g., 5%, optionally in combination with dextrosee.g., 10% or NaCl e.g., 15 or 20%; multiple electrolyte solutions withvarying combinations of electrolytes, dextrose, fructose, invert sugarRinger's e.g., NaCl 0.86%, KCl 0.03%, CaCl₂ 0.033%; sodium bicarbonatee.g., 5%; sodium chloride e.g., 0.45, 0.9, 3, or 5%; sodium lactatee.g., 1/6 M; and sterile water for injection The pH of such IV fluidsmay vary, and will typically be from about 3.5 to about 8 as known inthe art.

The dose of tramadol or pharmaceutically acceptable salts thereof can beadministered alone or in combination with other medical treatments, orother therapeutic agents, such as NSAIDs. When so-used, othertherapeutic agents can be administered before, concurrently (whether inseparate dosage forms or in a combined dosage form), or afteradministration of an active agent of the present invention.

Consistent with the known clinical effects of opioids, nonclinicalsafety pharmacology studies have shown that tramadol at high dosesaffects the central nervous system (CNS), producing sedation, impairedmobility, vomiting (dogs), decreased activity, and convulsions(Matthiesen et al., 1998). Also consistent with clinical effects,changes in blood pressure have been observed in cardiovascular studiesin rats at high doses (Raimundo et al., 2006). Tramadol use,particularly with high doses, has been associated with seizures, and therisk of seizures is increased in the presence of drugs that reduceseizure threshold, head trauma or prior history of seizures.

The toxicity of tramadol has been summarized by Matthiesen, et al.(1998). The single-dose toxicity of tramadol was similar in all speciestested, independent of the route of administration. Notable acutefindings included restlessness, unsteady gait, reduced spontaneousactivity, exophthalmus, mydriasis, salivation, vomiting (dog), tremor,convulsions, slight cyanosis and dyspnea. The principle findings inrepeat-dose toxicity studies in rats and dogs were behavioral/clinicalsigns and convulsions at doses of ≥25 mg/kg/day. The kidney and liverwere identified as potential target organs in rats, with mild effects(minimal tubular vacuolization and perivenular hydropic degeneration,respectively) following repeat intraperitoneal dosing at high doses oftramadol.

There was no evidence of genotoxic potential for tramadol in standard invitro and in vivo studies (Matthiesen et al., 1998). Carcinogenicitybioassays in mice and rats showed no evidence of carcinogenic potential.An extensive reproductive and teratology program revealed no safetyconcerns with respect to fertility or teratogenic effects after oraladministration (Matthiesen et al., 1998; Yamamoto et al., 1972).Toxicity to offspring only occurred at doses associated with maternaltoxicity.

Following oral administration, tramadol is rapidly and almost completelyabsorbed. The pharmacokinetics of tramadol were evaluated in healthymale volunteers (n=10) in a crossover design using 100 mg PO or IV doses(Lintz et al., 1986). Peak serum concentrations (tmax) were reachedapproximately 2 hours after oral dosing and the peak serum concentration(Cmax) for PO tramadol was 280±49 ng/mL. The terminal half-life was 5.1hours for PO and 5.2 hours for IV administration. The area under theserum tramadol concentration-time curve (AUC) was 2488±774 ng·h/mL forPO and 3709±977 ng·h/mL for IV administration. Total clearance was467±124 mL/min for PO and 710±174 mL/min for IV administration. Theabsolute bioavailability of the oral dose was 68±13%, based oncomparison of the AUC values, while the estimated absorption of the oraldose was 86-88%. The difference between absorption and bioavailabilitywas attributed to first pass metabolism, which was estimated to be ˜20%.However, the absolute bioavailability approaches 90-100% with continuousdosing, probably due to saturation of first pass metabolism (Liao etal., 1992). Other studies have corroborated these findings (Grond andSablotzki, 2004).

The pharmacokinetic profile of tramadol following i.v. and p.o.administration in humans (n=10, male) is summarized in Table A below(Lintz W, Barth H, Osterloh O, Schmidt-Bothelt E. Bioavailability ofenteral tramadol formulations. 1st communication: capsules. ArzneimForsch Drug Res. 1986; 36:1278-1283). The absolute oral bioavailabilityof tramadol was 68% (±13) in humans.

TABLE A Pharmacokinetics of Tramadol (100 mg) Following Intravenous andOral Administration to Humans Tramadol C_(max) t₁/₂ AUC_(0-24 h) V_(d)CL/F (100 mg) (ng/mL) (h) (ng · h/mL) (L) (mL/min) i.v. — 5.2 ± 0.8 3709± 977 203 ± 40 467 ± 124 p.o 280 ± 49 5.1 ± 0.8 2488 ± 774 306 ± 52 710± 174 Abbreviations: C_(max), maximal concentration; t_(1/2), half-life;AUC, area under the plasma concentration-time curve; CL, clearance; F,bioavailability; V_(d;) volume of distribution

The pharmacokinetic profile of tramadol and the (+)-M1 and (−)-M1metabolites was also evaluated in humans (N=12, male) following p.o.administration of a single 1.5 mg/kg dose of tramadol (Matthiesen, etal., 1993). The data are summarized in Table B below:

TABLE B Pharmacokinetics of Tramadol and the (+) and (−) Enantiomers ofthe M1 Metabolite Tramadol (1.5 mg/kg, C_(max) T_(max) t₁/₂ AUC CL/F[100 mg]) (ng/mL) (h) (h) (ng · h/mL) (mL/min/kg) Tramadol 274 ± 1.6 ±5.9 ± 2177 ± 742 ± 75 0.5 0.7 722 234 (+)-M1 147 ± 1.6 ± 6.0 ± 1258 ±642 ± 39 0.5 1.0 410 204 (−)-M1 125 ± 1.5 ± 5.2 ± 908 ± 883 ± 32 0.5 0.8298 264 Abbreviations: C_(max), maximal concentration; T_(max), time tomaximal concentration; AUC, area under the plasma concentration-timecurve; CL, clearance; F, bioavailability; t₁/₂, half-life; V_(d); volumeof distribution

Tramadol undergoes hepatic metabolism and both the parent drug and theactive metabolite are excreted by the kidneys. The active metabolite, M1(O desmethyltramadol), is produced by the action of CYP2D6 isozyme ofthe cytochrome P450 enzyme system. It has a half-life of approximately6.7 hours after oral administration (single dose of 100 mg), compared toa half-life of 5.6 hours for tramadol administered intravenously.Hepatic impairment results in decreased metabolism of both the parentcompound and the active metabolite. Tramadol is rapidly distributedafter IV administration with a distribution half-life in the initialphase of 0.31±0.17 hours, followed by a slower distribution phase with ahalf-life of 1.7±0.4 hours (Lintz et al., 1986). The volumes ofdistribution following PO and IV administration were 306 L and 203 L,respectively, indicating that tramadol has a high tissue affinity. Theprotein binding of tramadol is approximately 20%; however, saturation ofbinding sites does not occur in the therapeutic dose range (Ultram®Prescribing Information, 2009).

Elimination half-life increases approximately 2-fold in subjects withrenal or hepatic impairment. Patients who metabolize drugs poorly viaCYP2D6 (Caucasian population prevalence ˜8%) may obtain reduced benefitfrom tramadol due to reduced formation of M1 (Ultram® PrescribingInformation, Ortho-McNeil-Janssen Pharmaceuticals, Inc, 2009).

Studies of IV tramadol in the postoperative setting have shown anacceptable safety profile. Loading doses up to 150 mg IV were notassociated with any serious adverse effects (Silvasti et al., 2000).Also, no serious adverse effects were observed in clinical trials oftramadol with mean (±SD) cumulative doses of 449±66 mg (Rud et al.,1994), 677±473 mg (range 128-1750 mg) (Silvasti et al., 2000), and868.3±412.2 mg (Pang et al., 1999) over 24, 36 and 48 h respectively.

The most common adverse events, nausea, dizziness, headache, somnolence,sweating, fatigue, constipation, dry mouth and vomiting, which areusually mild to moderate in severity and only occasionally lead topremature discontinuation of tramadol.

The Ultram® and Tramal® labels contain several warnings and precautionsregarding use of tramadol. The risk of most of these potential adverseevents can be minimized by decreasing the dose or excluding use oftramadol in subjects with risk factors associated with these known, rareadverse events. Tramadol metabolism is reduced in the setting ofadvanced cirrhosis and renal clearance of both tramadol and itsmetabolites is reduced in individuals with creatinine <30 mL/min. Thus,the dose of tramadol should be reduced by half or the interval doubledin these populations. Dosage adjustment is also recommended inindividuals >75 years of age as they have reduced drug clearance.Tramadol is metabolized by CYP2D6 and CYP3A4; thus, drugs that areinhibitors or inducers of these enzymes can alter tramadol metabolism,resulting in decreased efficacy and/or increased risk of seizures orother adverse effects. Tramadol is associated with a low risk forrespiratory depression, which is increased in the presence of otheropioids, anesthetic agents and other CNS depressants, including alcohol.Respiratory depression due to the opioid activity of tramadol can bereversed with naloxone. Naloxone should be used cautiously as it canpotentiate seizures when administered with tramadol. The full range ofallergic/hypersensitivity reactions have been reported in associationwith tramadol administration, including serious and rarely fatalanaphylactoid reactions.

Potentially life-threatening serotonin syndrome may occur with tramadolproducts with concomitant use of serotonergic drugs such as SSRIs,tricyclic antidepressants, monoamine oxidase inhibitors and triptans.

Tramadol use, particularly with high doses, has been associated withseizures, and the risk of seizures is increased in the presence of drugsthat reduce seizure threshold, head trauma or prior history of seizures.

Human studies evaluating the abuse potential of tramadol, administeredvia IV or PO routes, have also been conducted (Epstein et al., 2006).During the initial dose-ranging studies, seizure was observed followinga tramadol dose of 700 mg IV administered over 1 minute and 300 mg IVdelivered over 2.5 minutes. No seizures were observed with a tramadoldose of 200 mg IV administered over 5 minutes. The authors hypothesizedthat toxicity is likely to limit abuse of high doses of IV tramadol. Ina subsequent study involving 10 experienced opioid abusers, tramadol(100 and 200 mg IV), morphine (10 and 20 mg IV) and placebo wereadministered over 5 minutes. The endpoints in the study were subjective;the extent to which subjects “liked” the effects of the drugs, as wellas their ability to produce effects common to morphine and benzadrine(assessed by the Addiction Research Center Inventory-Morphine BenzadrineGroup [ARCI-MBG] scale). Tramadol and morphine significantly increasedratings of “feel drug effect” compared to placebo. However, neither doseof tramadol increased ratings on the “liking” or ARCI-MBG scale or onany other subjective measure of opiate-like effects. In contrast,morphine 10 and 20 mg doses significantly increased ratings of “liking”and the morphine 20 mg dose increased ratings on the ARCI-MBG scale.Thus, tramadol administered via the parenteral route (IV or IM) isunlikely to be associated with the subjective morphine-like and positivemood effects typical of abuse and addiction.

In accordance with the present invention, it is desirable to provide anintravenous dosing regimen of tramadol which at steady-state provides aplasma concentration with respect to Cmax and AUC that is similar orequivalent to the steady-state Cmax and AUC provided by a 100 mg oraltramadol dose given every 6 hours would be desirable and would be saferand have less likelihood of significant side effects than, e.g., theadministration of 100 mg of tramadol intravenously administered every 6hours (i.e., same dose and dosing interval as the oral referencestandard, Ultram®. It is further believed that it would desirable forsuch an intravenous dosing regimen(s) to provide a steady-state troughplasma level of tramadol (e.g., Cmin) which is at least as high as thesteady-state trough level provided by a 100 mg oral tramadol dose givenevery 6 hours. It is further desirable in accordance with the presentinvention to provide a dosing regimen which reaches but does notsubstantially exceed the maximum (Cmax) and minimum (Cmin) plasma levelsof tramadol obtained at steady-state by a 100 mg oral tramadol dosegiven every 6 hours as soon as possible within the dosing regimen, e.g.,prior to the end of the initial 24 hours of intravenous tramadol, orsooner. As will be explained further herein, for purposes of the presentinvention the steady-state Cmax of the 100 mg oral dose of tramadoladministered every 6 hours is about 736 ng/mL. For purposes of thepresent invention, a similar or equivalent Cmax provided by anintravenous tramadol dosing regimen would provide a Cmax within therange from about 80% to about 125% of the steady-state Cmax of the 100mg oral tramadol administered every 6 hours (e.g., 736 ng/mL; or e.g.,from about 588.8 ng/mL to about 920 ng/mL). It is especially preferredthat the steady-state Cmax of the dosing regimen(s) of the presentinvention do not exceed the concentration provided by 100 mg oraltramadol administered every 6 hours, at steady-state (e.g., about 701ng/mL) by more than 15% or more than about 10%.

It is further preferred that the intravenous dosing regimen of tramadolof the present invention at steady-state provides a plasma concentrationwith respect to Cmax and AUC of the M1 metabolite of tramadol that issimilar or equivalent to the steady-state Cmax and AUC of the M1metabolite provided by a 100 mg oral tramadol dose given every 6 hours,as it is known that the M1 metabolite significantly contributes to theanalgesic efficacy of the tramadol formulation. It is further believedthat it would desirable for such an intravenous dosing regimen(s) toprovide a steady-state trough plasma level of the M1 metabolite oftramadol (e.g., Cmin) which would be therapeutically effective, or whichis similar (e.g., from about 20% to about 125%, or from about 60% toabout 125%, or from about 80% to about 125%) of the steady-state troughlevel of the M1 metabolite provided by a 100 mg immediate release oraltramadol dose given every 6 hours. It is further desirable in accordancewith the present invention to provide a dosing regimen which reaches butdoes not substantially exceed the maximum (Cmax) and minimum (Cmin)plasma levels of the M1 metabolite of tramadol obtained at steady-stateby a 100 mg oral tramadol dose given every 6 hours as soon as possiblewithin the dosing regimen, e.g., prior to the end of the initial 24hours of intravenous tramadol, or sooner. As will be explained furtherherein, for purposes of the present invention the steady-state Cmax ofthe M1 metabolite for 100 mg oral dose of tramadol administered every 6hours is about 146 ng/mL±37.4. For purposes of the present invention, asimilar or equivalent Cmax of the M1 metabolite provided by anintravenous tramadol dosing regimen would be, e.g., within the rangefrom about 20% to about 125%, or from about 60% to about 125%, or fromabout 80% to about 125% of the steady-state Cmax of the 100 mg oraltramadol administered every 6 hours (about 146 ng/mL). It is especiallypreferred that the steady-state M1 metabolite Cmax of the dosingregimen(s) of the present invention does not exceed the 146 ng/mLconcentration by more than 10%, or (in certain embodiments) does notexceed the 146 ng/mL level at all during the dosing regimen.

In further preferred embodiments of the present invention, the Cmax andCmin levels obtained during the initial 24 hour dosing interval aregreater than or similar to the Cmax and Cmin levels obtained during theinitial 24 hour dosing interval for a 100 mg immediate release oraltramadol dose given every 6 hours, but not significantly greater thanthe steady-state Cmax level for a 100 mg immediate release oral tramadoldose given every 6 hours.

In accordance with the present invention, the intravenous tramadoldosing regimens of the present invention and as described herein will besimilar to, match or exceed the analgesic efficacy of a 100 mg immediaterelease oral tramadol dose given every 6 hours, but may reduce sideeffects and/or may improve tolerance as compared to that oralformulation.

The above goals and others are achieved by the present invention,wherein the dose of tramadol is reduced relative to the approved oraldose (100 mg) in the U.S., with the addition of at least one loadingdose administered in a shortened dosing interval as compared to thereference standard (Ultram® 100 mg oral tablets). By decreasing the doseof tramadol but increasing the number of administrations during theinitial 24 hour period of tramadol administration, the present inventionachieves the goal of a lowered dose providing similar Cmax, AUC andefficacy as compared to the orally administered 100 mg tramadol Q6h.

In a preferred embodiment, the dosing regimen comprises 50 mg IVtramadol at hour 0, followed by 50 mg at hour 2, 50 mg at hour 4, and 50mg every 4 hours thereafter (e.g., until the patient no longer requirestreatment with tramadol). In this embodiment, the maximum plasmaconcentration (Cmax) of the tramadol rapidly approaches the maximumconcentration found at steady-state with respect to a dosing regimen of100 mg tramadol HCl administered orally every 6 hours. The Cmax obtainedafter the third dose of 50 mg IV tramadol (Cmax₄₋₆) is approximately thesame as the Cmax at steady-state for a dosing regimen of 100 mg tramadolHCl administered orally every 6 hours. However, in contrast, the oraltramadol dosing regimen takes considerably longer (Cmax₄₄₋₄₈) to reachthat maximum tramadol plasma concentration. As demonstrated in Example 5herein, the Cmax of the 50 mg IV tramadol dosing regimen is about 736ng/mL±152 and is approached during the third dose (see, e.g., Example 5,Table 11 and FIGS. 11-12), whereas the Cmax of tramadol for the oral 100mg dosing regimen is about 701 ng/ml±178 and occurs at 42-48 hours afterthe first oral dose is administered (see, e.g., Example 5, Table 11 andFIGS. 9 and 12). Moreover, in this embodiment the trough levels (plasmaconcentrations of tramadol) also much more rapidly reach a level similarto the trough levels at steady-state for the oral 100 mg every 6 hoursdosing regimen. It is believed that the fact that (for the 50 mg IVdosing regimen) peak and trough plasma levels similar to steady-statelevels found for the oral 100 mg q6h dosing regimen are reached at asuch an earlier time may translate into improved efficacy (pain relief)for the patients.

It is further believed that the intravenous dosing regimen of theinvention, e.g., as a slow push of a therapeutically effective dose oftramadol contained in a bag over a time period from about 10 to about 20minutes, preferably about 15 minutes, will provide added safety withrespect to the above-mentioned potential adverse events and others, andwill provide lower incidence of side effects associated with tramadoladministration. It is further believed that the intravenous dosingregimen of the invention where a therapeutically effective dose oftramadol is administered to a human patient(s) over a time period fromabout 24 hours to 48 hours in much slower infusion will also providethese benefits.

The intravenous tramadol formulation in accordance with the inventiontypically includes tramadol in the form of its hydrochloride salt.However, one of ordinary skill in the art will appreciate that otherforms of tramadol may be used, including but not limited to allpharmaceutically acceptable salts of tramadol. Such pharmaceuticallyacceptable salts may include, but are not limited to, metal salts suchas sodium salt, potassium salt, secium salt and the like; alkaline earthmetals such as calcium salt, magnesium salt and the like; organic aminesalts such as triethylamine salt, pyridine salt, picoline salt,ethanolamine salt, triethanolamine salt, dicyclohexylamine salt,N,N′-dibenzylethylenediamine salt and the like; inorganic acid saltssuch as hydrochloride, hydrobromide, sulfate, phosphate and the like;organic acid salts such as formate, acetate, trifluoroacetate, maleate,tartrate and the like; sulfonates such as methanesulfonate,benzenesulfonate, p-toluenesulfonate, and the like; amino acid saltssuch as arginate, asparginate, glutamate and the like.

It is contemplated that with respect to the inventive methods for theintravenous administration of tramadol as described herein, otheranalgesics, preferably opioid analgesics, may be used to treatpostoperative pain in the patient(s), as well. It is particularlycontemplated that one or more opioid analgesics will be administeredpost-surgically to the patient as rescue medicine in order to treatbreakthrough pain that the patient may experience.

The term “opioid analgesic” refers to all drugs, natural or synthetic,with morphine-like actions. The synthetic and semi-synthetic opioidanalgesics are derivatives of five chemical classes of compound:phenanthrenes; phenylheptylamines; phenylpiperidines; morphinans; andbenzomorphans, all of which are within the scope of the term. Opioidanalgesics which are useful in the present invention include all opioidagonists or mixed agonist-antagonists, partial agonists, including butnot limited to alfentanil, allylprodine, alphaprodine, anileridine,benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene,codeine, desomorphine, dextromoramide, dezocine, diampromide,diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, fentanyl, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, narceine, nicomorphine,norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine,norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, propheptazine, promedol, properidine, propoxyphene,sufentanil, tilidine, mixtures of any of the foregoing, salts of any ofthe foregoing, and the like.

In certain preferred embodiments, opioid analgesics include morphine,oxycodone, codeine, dihydrocodeine, diacetylmorphine, hydrocodone,hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine,butorphanol, fentanyl, sufentanyl, meperidine, methadone, nalbuphine,propoxyphene and pentazocine or pharmaceutically acceptable saltsthereof. In certain preferred embodiments, the opioid agonist ismorphine. Equianalgesic doses of these opioids are generally known tothose persons having ordinary skill in the art.

In certain embodiments, the patient's need for additional analgesictreatment beyond the intravenous tramadol may be ascertained via the useof a surrogate measure of pain. Pain rating scales are used in dailyclinical practice to measure pain intensity. The commonly usedmeasurement scales include the Visual Analog Scale (VAS), the GraphicRating Scale (GRS), the Simple Descriptor Scale (SDS), the NumericalRating Scale (NRS), and the Faces Rating Scale (FRS). All of thesescales have been documented as being valid measures of pain intensity.The three scales most commonly used in the U.S. are the numerical, wordand faces scales. One preferred pain rating scale is the visual analogscale (VAS), a 10 cm. vertical or horizontal line with word anchors atthe extremes, such as “no pain” on one end and “pain as bad as it couldbe” at the other. The patient is asked to make a mark along the line torepresent pain intensity.

Alternatively, the graphic rating scale (GRS) is a variation of thevisual scale which adds words or numbers between the extremes. Wordingadded might include “no pain”, “mild”, “severe”. The descriptor scale(SDS) is a list of adjectives describing different levels of painintensity. For example pain intensity may be described as “no pain”,“mild”, “moderate” or “severe”. The numerical pain rating scale (NPRS)refers to a numerical rating of 0 to 10 or 0 to 5 or to a visual scalewith both words and numbers. The patient is asked to rate the pain with0 being no pain and 10 being the worst possible pain. The faces scalewas developed for use with children. This scale exists in severalvariations but relies on a series of facial expressions to convey painintensity. Grouping patients' rating of pain intensity as measured witha numerical scale ranging from 0 to 10 into categories of mild,moderate, and severe pain is useful for informing treatment decisions,and interpreting study outcomes. In 1995, Serlin and colleagues (Pain,1995, 277-84) developed a technique to establish the cut points formild, moderate, and severe pain by grading pain intensity and functionalinference. Since then, a number of studies have been conducted tocorrelate the numerical scales, for example the NPRS, with cutpointsrelated to levels of pain intensity. Common severity cutpoints are (1 to4) for mild pain, (5 to 6) for moderate pain, and (7 to 10) for severepain.

Surrogate measures of opioid efficacy (analgesia) include sedation,respiratory rate and/or pupil size (via pupillometry), and visualanalogue scale (“VAS”) for “drug effect”. The Sum of Pain IntensityDifferences (SPID) through 48 hours post first dose (SPID48) at rest maybe used as a primary measure of efficacy.

The intravenous tramadol dosing regimens of the invention may be used inthe in the hospital or day hospital setting and therefore administeredby medical staff. The tramadol hydrochloride injection for intravenoususe and its dosing regimen can fill an important need in addition totramadol (e.g., ULTRAM®) tablets and tramadol (e.g., ULTRAM® ER)extended-release tablets by providing this safe and effective injectableanalgesic with a novel mechanism of action (μ-opioid agonist andmonoaminergic reuptake inhibition) for use in the acute post-operativesetting. These dosing regimens may be used, e.g., for all types ofsurgery, including orthopedic surgery (e.g., total knee replacement,bunionectomy) or soft tissue surgery (e.g., elective abdominoplasty).

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

This invention is further illustrated by the following examples thatshould not be construed as limiting. Those of skill in the art ofpharmaceutical formulation will readily appreciate that certainmodifications to the examples may be readily effected. Any methods,materials, or excipients which are not particularly described will begenerally known and available those skilled in the drug design and assayand pharmacokinetic analysis.

Example 1

The purpose of this analysis was to calculate the systemic exposure oftramadol and its active metabolite M1, when given as an intravenous (IV)infusion that would provide an AUC and Cmax that are comparable toimmediate release oral tramadol HCl 100 mg administered every 6 hours(e.g., Ultram® 100 mg IR q6h).

Tramadol is extensively metabolized by CYP2D6 and CYP3A4. Onemetabolite, M1, is 6 times more potent than the parent compound inproducing analgesia and 200 times more potent in μ opioid binding inanimal model. For PK modeling purposes, tramadol level (Cmax) wasconsidered to be the most important parameter, as it is most directlyrelated to seizure risks. Due to first pass metabolic saturation,steady-state plasma concentration exceeds that of a single doseadministration. Steady-state is reached in about 42-48 hours. For PKmodeling purposes, the dose proportionality study previously reported inthe assignee's U.S. Pat. No. 8,895,622 was used as basis for themodeling.

Using the compartment model for tramadol and M1, a 62 mg dose wasestimated to result in a C_(max) close to what was observed for a 100 mgoral dose (geometric mean oral C_(max)=676 ng/mL). It was concluded thatthe infusion rate did not affect the calculated AUC₆ for either analyte,and that the C_(max) for both analytes were fairly insensitive to viableinfusion durations of 10 to 20 minutes (the modeled Cmax was 680 ng/mLfor a 10 minute infusion time, 678 ng/mL for a 15 minute infusion time,and 670 ng/mL for a 20 minute infusion time). Since an infusion durationin the 10 to 20 minute range did not influence the C_(max) of eithertramadol or the M1 metabolite, a linear model and a power model wereinvestigated vs. the effect of dose alone.

The critical threshold values for C_(max) and AUC₆ (the AUC or “areaunder the curve” predicted after 6 doses) resulting from 50 mg and 100mg (60 mg and 120 mg dose by extrapolation) oral doses of tramadol arepresented in Table 1. The predicted oral dose to achieve threshold PKparameters is shown in Table 2. Table 3 lists the various predicted IVdoses required to reach the various threshold values for a given PKparameter. For example, a 30 mg IV dose would result in a similarC_(max) value as a 50 mg oral dose. An 81 mg IV dose would result insimilar M1 AUC value as that observed for one 100 mg oral dose. In allcases, the tramadol C_(max) threshold is reached using the lowest IVdose, therefore it was considered that the lowest dose is the definingdose.

TABLE 1 PK Parameters for 50 mg and 100 mg Oral Tramadol Threshold PKParameters Tramadol M1 Oral Dose C_(max) AUC₆ C_(max) AUC₆ (mg) (ng/mL)(hr*ng/mL) (ng/mL) (hr*ng/mL) 50 340 1641 96 491 60 408 1969 115 589 100676 3230 125 668 120 811 3876 150 802

TABLE 2 Linear Model: Calculated Dose Required to Reach PK Parametersfor 50 mg and 100 mg Oral Tramadol Predicted Dose to Achieve ThresholdPK Parameter Tramadol M1 Oral Dose C_(max) AUC₆ C_(max) AUC₆ (mg) (mgDose) (mg Dose) (mg Dose) (mg Dose) 50 30 39 61 59 60 36 47 73 71 100 5977 80 81 120 71 92 96 97

TABLE 3 Linear Model: PK Parameters at Predicted Threshold Dose Requiredto Reach Equivalent C_(max) for 50 mg and 100 mg Oral Tramadol PredictedPK Parameters Tramadol M1 Dose (mg) C_(max) AUC₆ C_(max) AUC₆ Oral IV(ng/mL) (hr*ng/mL) (ng/mL) (hr*ng/mL) 50 30 342 1263 47 248 60 36 4101515 57 298 100 59 673 2483 93 488 120 71 810 2988 111 587

The confidence intervals for Cmax resulting from IV administration wasnarrower than that seen after oral administration. The 90% confidenceinterval for a 65-mg IV dose lies within that of the Cmax resulting fromadministration of the 100 mg oral dose.

The results for Example 1 led to the conclusion that IV 60 mg q6hprovides a Cmax comparable to the referenced product (oral IR 100 mgtramadol HCl) but with a much lower AUC and M1 levels. Since the M1metabolite is known to provide a significant contribution to analgesia,and a lower AUC is predicted to reduce efficacy, further researchregarding a useful IV formulation that would provide a Cmax comparableto the referenced product but having a greater likelihood of providingthe desired efficacy was desired.

Example 2

In this Example, the administration of tramadol and its activemetabolite M1 were evaluated using model simulated parameters, whenadministered as a 15-minute intravenous (IV) infusion of tramadol every4 hours using a compartmental model previously developed to describe thepharmacokinetics of the parent drug tramadol and its M1 metabolite asadministered Q6h, with the goal of the intravenous dosing regimen toprovide a Cmax and AUC of tramadol which is similar to the Cmax and AUCof an oral dose of 100 mg tramadol HCl given every 6 hours. In thisExample, a 48 mg IV infusion administered every 4 hours and a 62 mg IVinfusion administered every 4 hours were modeled.

The geometric mean at steady-state for Cmax and AUC6 of tramadol and M1resulting from the simulated IV infusion given Q4h at a dose of 48 mgwas similar to that observed at Q6h for the 100 mg oral dose. Thepercent of PK value at steady-state of tramadol for the simulated IVinfusion administered Q4h at 48 mg was slightly lower for Cmax andsimilar for AUC6 to that of the 100 mg oral dose (Table 4 and Table 5).

TABLE 4 Geometric Mean: Steady-State Tramadol C_(max) and AUC₆ forObserved Oral Dose and Simulated IV Infusion Tramadol M1 C_(max) AUC₆*C_(max) AUC₆ Administration (ng/mL) (hr*ng/mL) (ng/mL) (hr*ng/mL) 100 mgOral Dose Q6h 676 3230 125 668 48 mg IV Infusion Q4h 672 2904 102 594 62mg IV Infusion Q6h 678 2509 91 514 *Steady-state AUC₆ for Q4h calculatedfrom C_(avg)*6 hr

TABLE 5 Percent of Steady-State PK Value with Respect to the 100 mg OralDose Tramadol M1 C_(max) AUC₆ C_(max) AUC₆ Percent of PK Value withRespect Administration to the 100 mg Oral Dose 48 mg IV Infusion Q4h 99% 90% 82% 89% 62 mg IV Infusion Q6h 100% 78% 73% 77%

The results of the modeling as depicted in Tables 1 and 2 show thatincreasing the frequency of dosing from every 6 hours to every 4 hoursnecessitated a lowering of the dose, as a 62 mg dose Q4h would result ina mean steady-state Cmax value of 868 ng/mL (not shown) which iswell-above the Cmax of the 100 mg oral dose of 676 ng/mL. After carryingout various simulations, a 48-mg 15 minute infusion every 4 hours wasfound to result in a similar Cmax value to that of the 100 mg oral dose.In addition, the 48 mg Q4h dosing regimen allowed the tramadol AUC6 tomore closely resemble that of the 100 mg oral Q6h. The results show thattramadol given as a 48 mg every 4 hours offers a significant advantageover the 62 mg every 6 hours in that the tramadol AUC6 increased to 90%of the 100 mg oral value. The more frequent administration regime hasthe added benefit of higher trough levels of tramadol, avoiding thepossibility of sub-therapeutic concentrations.

The geometric mean of tramadol concentrations at steady-state whenadministered Q6h and Q4h are presented in FIG. 1.

Example 3

In Example 3, three different dosing regimens were modeled based on theresults in Examples 1 and 2. In Examples 3a-3c, a 50 mg intravenoustramadol dose was modeled via administration every 4 hours.

In Example 3a (“100 mg Loading Dose”), a 100 mg intravenous tramadolloading dose was first administered, and then a 50 mg intravenoustramadol dose is administered 4 hours later. Thereafter, the intravenoustramadol is administered as a 50 mg dose every 4 hours (100 mg dose,followed by 50 mg q4h).

In Example 3b (“50 mg Loading at 2 hr”), a 50 mg tramadol dose isinitially administered (at 0 hours). Therefore, in this dosing regimen,a 50 mg intravenous tramadol dose is administered 2 hours after theinitial 50 mg dose (as a second dose). Another 50 mg intravenous dose isadministered 2 hours after the second dose. Thereafter, 50 mgintravenous tramadol is administered every 4 hours. (50 mg at T0, 50 mgat T2, followed by 50 mg at T4, T8 . . . ).

In Example 3c (“1st Dosing Interval 2 hr”), a 50 mg tramadol dose isinitially administered (at 0 hours). Therefore, in this dosing regimen,a 50 mg intravenous tramadol dose is administered 2 hours after theinitial 50 mg dose (as a second dose). Another 50 mg intravenous dose isadministered 4 hours after the second dose. Thereafter, 50 mgintravenous tramadol is administered every 4 hours. (50 mg at T0, 50 mgat T2, followed by 50 mg at T6, T10 . . . ).

In Table 6, the geometric mean Cmax (ng/mL) values of Examples 3a-3c aremodeled, using the various loading doses explained above, and comparedagainst a 50 mg dose given every 4 hours with no loading dose:

TABLE 6 0 hr 2 hr 4 hr 6 hr 8 hr 10 hr to 2 hr to 4 hr to 6 hr to 8 hrto 10 hr to 12 hr No Loading 311 433 507 Dose Steady-State 700 700 70050 mg Q4 h 100 mg 621 555 580 Loading Dose 50 mg Loading 311 484 605 599at 2 hr 1rst Dosing 311 484 526 567 Interval 2 hr

FIG. 2 is a graphical representation of the modeled plasma curve ofExample 3a (100 mg loading dose) plotted against the plasma curveprovided by a 100 mg oral tramadol dose given every 6 hours. The peakconcentration of Example 3a during the first dosing interval approachesthe peak concentration for a 100 mg oral tramadol dose given every 6hours, at steady-state, but does not exceed that level. Also, the troughlevels provided after the first and second doses are higher than thetrough concentrations provided at the end of the first dosing intervalfor a 100 mg oral tramadol dose given every 6 hours.

FIG. 3 is a graphical representation of the modeled plasma curve ofExample 3b (50 mg loading at 2 hr) plotted against the plasma curveprovided by a 100 mg oral tramadol dose given every 6 hours. It can beseen in FIG. 3 that the first peak plasma concentration of Example 3bdepicted in the graph is similar to the first peak plasma concentrationprovided by a 100 mg oral tramadol dose given every 6 hours. On theother hand, the trough concentrations provided by Example 3b are higherthan the trough concentrations provided at the end of the first dosinginterval for a 100 mg oral tramadol dose given every 6 hours. This dataindicates to one of skill in the art that the dosing regimen of Example3b is a useful manner to administer IV tramadol to match the plasmaconcentration curve of oral tramadol, while improving tolerance andreducing side effects.

With respect to the modeled plasma curve of Example 3c (1st DosingInterval 2 hr) as compared against the plasma curve provided by a 100 mgoral tramadol dose given every 6 hours, the first peak plasmaconcentration of Example 3c is similar to the first peak plasmaconcentration provided by a 100 mg oral tramadol dose given every 6hours. On the other hand, the trough concentrations provided by Example3c are higher than the trough concentrations provided at the end of thefirst dosing interval for a 100 mg oral tramadol dose given every 6hours. This data indicates to one of skill in the art that the dosingregimen of Example 3b is a useful manner to administer IV tramadol tomatch the plasma concentration curve of oral tramadol, while improvingtolerance and reducing side effects. However, the trough concentrationsof Example 3b are significantly higher than the trough concentrations ofExample 3c, while the peak concentrations of Example 3b are lower thanthe steady-state peak plasma concentration provided by a 100 mg oraltramadol dose given every 6 hours, but yet greater than the peakconcentrations of Example 3c over the same time interval. This datawould lead one of skill in the art to prefer Example 3b over Example 3c.

Example 4

In Example 4, a simulation was conducted in order to compare a 75 mg IVtramadol dosing regimen using a 15 minute infusion every 6 hours (Q6h)with an additional dose at three hours, and the comparison ofsteady-state pharmacokinetic profiles of tramadol and M1 obtained withthat dosing regimen to 100 mg oral tramadol Q6h.

Table 7 provides the modeled geometric mean Cmax and AUC values for bothtramadol and its M1 metabolite and compares the same to thepharmacokinetic values of 100 mg oral tramadol Q6h.

TABLE 7 Analyte Tramadol M1 C_(max) AUC C_(max) AUC Dose Time Interval(ng/mL) (hr*ng/mL) (ng/mL) (hr*ng/mL) 75 mg 0-3 hr 485 948 34 65 IV 3-6hr 710 1498 69 171 6-12 hr 855 3059 99 551 12-18 hr 813 2981 106 600Steady-State 821 3035 110 622 100 mg Steady-State 676 3230 125 668 Oral*

FIG. 4 is a graphical representation of the simulated tramadol plasmalevels of Example 4 plotted against the plasma concentration curves fora 100 mg and a 50 mg oral tramadol dose administered every 6 hours, atsteady-state. In FIG. 4, the reference plasma concentration of 676 ng/mlis the tramadol geometric mean steady-state Cmax value resulting from100 mg oral tramadol administered every 6 hours.

FIG. 5 is a graphical representation of the simulated M1 metaboliteplasma levels of Example 4 plotted against the M1 metabolite plasmaconcentration curves for a 100 mg and a 50 mg oral tramadol doseadministered every 6 hours, at steady-state. In FIG. 5, the referenceplasma concentration of 676 ng/ml is the tramadol geometric meansteady-state Cmax value resulting from 100 mg oral tramadol administeredevery 6 hours.

FIG. 6 is a graphical representation of the simulated plasmaconcentration of Example 4 over the initial 24 hours. In FIG. 6, thereference plasma concentration of 676 ng/ml is the tramadol geometricmean steady-state Cmax value resulting from 100 mg oral tramadoladministered every 6 hours. It can be seen that by the third dose of themodeled Example 4 (75 mg doses), the Cmax is reached which is equivalentto the steady-state Cmax of the 100 mg oral tramadol administered every6 hours.

FIG. 7 is a graphical representation of the simulated M1 metaboliteplasma concentration of Example 4 over the initial 24 hours. In FIG. 7,the reference M1 plasma concentration of 125 ng/mL is the M1 geometricmean steady-state Cmax value resulting from 100-mg oral doseadministered every 6 hours. It can be seen that by the fifth dose of themodeled Example 4 (75 mg doses), the Cmax is reached which is equivalentto the steady-state M1 metabolite Cmax of the 100 mg oral tramadoladministered every 6 hours.

FIG. 8 is a graphical representation of the simulated tramadol plasmaconcentration of Example 4 over the initial 24 hours, plotted againstthe tramadol plasma concentration of the 100 mg oral tramadoladministered every 6 hours, and the reference plasma concentration of676 ng/ml (which is the tramadol geometric mean steady-state Cmax valueresulting from 100 mg oral tramadol administered every 6 hours). Theinitial 24 hour oral data was digitally extracted from Yalda H. Ardakaniand Mohammad-Reza Rouini, “Pharmacokinetics of Tramadol and its ThreeMain Metabolites in Healthy Male and Female Volunteers” Biopharm. DrugDispos. 28: 526-533 (2007). Both IV and oral multiple doses weresimulated using semiparametric superposition method.

Table 8 provides the percent of pharmacokinetic value of Example 4 withrespect to 100 mg Oral Steady-State for Cmax and AUC for both tramadoland its M1 metabolite.

TABLE 8 Analyte Tramadol M1 C_(max) AUC C_(max) AUC Dose Time Interval(ng/mL) (hr*ng/mL) (ng/mL) (hr*ng/mL) 75 mg 0-3 hr  72% 29% 27% 10% IV3-6 hr 105% 46% 55% 26% 6-12 hr 126% 95% 79% 82% 12-18 hr 120% 92% 85%90% Steady-State 121% 94% 88% 93%

For comparative purposes, Table 9 provides the geometric mean Cmax andAUC values for both tramadol and its M1 metabolite.

TABLE 9 Analyte Tramadol M1 C_(max) AUC C_(max) AUC Dose Time Interval(ng/mL) (hr*ng/mL) (ng/mL) (hr*ng/mL) 75 mg 0-3 hr 485 948 34 65 IV 3-6hr 710 1498 69 171 6-12 hr 855 3059 99 551 12-18 hr 813 2981 106 600Steady-State 821 3035 110 622 100 mg Steady-State 676 3230 125 668 Oral*

The results of Example 4 may be summarized as follows. Tramadol AUC6, M1AUC6 and M1 Cmax are below the steady-state values observed for the100-mg oral dose. At steady-state, tramadol AUC6, M1 AUC6 and M1 Cmaxare similar but below the steady-state values observed for the 100 mgoral dose. At steady-state, the tramadol Cmax value (821 ng/mL) is abovethe 100 mg oral dosing regimen (676 ng/mL). Tramadol Cmax attains itshighest value at the 6 hour dosing interval of 855 ng/mL. Compared tothe 100 mg oral dosing, the IV dosing regimen (75 mg Q6h with anadditional dose at 3 hours) allows for a greater systemic exposure ofTramadol earlier on.

Example 5

In Example 5, a PK study in healthy volunteers was conducted to evaluatethe relative exposure of two intravenous (IV) dose regimens of tramadolcompared to the approved 100 mg Q6h oral dose regimen of tramadol. Thetwo tramadol IV dosing regimens were based on various pharmacokinetic(PK) simulations done prior to the study, and it was determined that thefollowing were appropriate for evaluation: (1) 75 mg IV REGIMEN: IVtramadol 75 mg administered at Hour 0, followed by 75 mg at Hour 3 andHour 6, and 75 mg every 6 hours thereafter through Hour 42; (2) 50 mg IVREGIMEN: IV tramadol 50 mg administered at Hour 0, followed by 50 mg atHour 2, 50 mg at hour 4, and 50 mg every 4 hours thereafter through Hour44. These two IV dosing regimens were studied in a multiple-dose,randomized, PK 3-way crossover study in 18 healthy volunteers, each ofwhom also received 100 mg oral tramadol given every 6 hours during oneof the periods through Hour 42.

Examination of the parent (tramadol) as well as the primary metabolite(M1 (O-desmethyltramadol) was performed over the 48-hour treatmentperiod. A focus of the analysis was on assessment of Cmax values (toensure the Cmax for the IV formulation was similar to that of the oralformulation) as well as on early concentrations during the first doses(to ensure adequate medication would be provided during the initial 6 to12 hours of treatment as the drugs reached steady-state concentrations).Overall exposure to tramadol was estimated from average trough plasmaconcentrations.

A fitted curve was obtained because the second oral peak was notmeasured in the study. For the modeling portion of the analysis, avalidated Phoenix® WinNonlin® program version 6.4 (Certara) was used forPK analysis, simulation, graphics, tables and statistical calculations.Tramadol plasma concentration-time data observed over the initial 24hours was fit to a linear 1-compartment model with first-orderabsorption and a lag time. For purposes of nonlinear regression, thedata were weighted as 1/observed. Predicted concentration-time data werecalculated based on the individual fitted PK parameters. The oral Cmaxand AUC values over the initial 12 and 24 hours after administration wascalculated using noncompartmental analysis of the predictedconcentration using a fitted model.

FIG. 9 provides the mean plasma tramadol time-concentration profiles forthe 100 mg oral, 50 mg IV, and 75 mg IV regimens. Mean plasma tramadolconcentrations just after administration (for example at 3, 6, and 42 h)were higher after 75 mg IV q6h compared to the administration of 50 mgIV q4h and 100 mg PO q6h. As evidenced from the trough/pre-dose samplesbetween 24 and 42 h, the mean tranomadol concentrations were verysimilar for 50 mg IV q4h and 100 mg PO q6h but somewhat lower for 75 mgIV q6h.

The mean tramadol concentrations for 50 mg IV q4h and 100 mg PO q6h werealmost superimposable at the end of the pharmacokinetic sampling period,between approximately 44 and 48 h, suggesting that the two regimensprovided similar steady-state concentrations (including trough and Cmaxconcentrations).

FIG. 10 provides the mean plasma O-desmethyltramadol time-concentrationprofiles for the 100 mg oral, 50 mg IV, and 75 mg IV regimen. The meanplasma O-desmethyltramadol concentrations were higher for 75 mg IV q6hfollowing the 3rd dose at 6 h, but there was appreciable overlap of thetrough concentrations for 75 mg IV q6h and 50 mg IV q4h between 24 and42 h. The pre-dose concentrations as well as the concentrations afterthe last dose at 42 h were higher for 100 mg PO q6h compared to both IVarms, presumably due to first pass metabolism which results in a higherfraction of the active metabolite in systemic circulation after oraladministration.

Select pharmacokinetic parameters (overall Cmax, Cmax at steady-state,trough at steady-state, AUC over the last dosing interval for eachregimen, ie, AUC_(tau n)) for tramadol are summarized in Table 10 below.

TABLE 10 Additional Plasma Pharmacokinetic Parameters of Tramadol 75 mgIV 50 mg IV 100 mg Oral Parameter n Mean SD CV % n Mean SD CV % n MeanSD CV % C_(max) (ng/mL) 14 932 199 21.30 14 736 152 20.60 17 701 17825.44 C_(max(42-48)) (ng/mL) 14 827 234 28.24 — — — — 17 701 178 25.44C_(max(44-48)) (ng/mL) — — — — 14 711 152 21.40 — — — — T₄₈ (ng/mL) 14354   85.9 24.31 14 448 131 29.36 17 497 144 29.09 Css (ng/mL) 14 506101 20.03 14 557 131 23.60 17 579 150 25.96

Exposure to O-desmethyltramadol was higher after 100 mg PO q6h comparedto either IV treatment, 50 mg IV q4h or 75 mg IV q6h. This was expected,considering the first pass metabolism after oral administration.Although exposure parameters were slightly higher for 75 mg IV q6hcompared to 50 mg IV q4h through early time points, exposure toO-desmethyltramadol was comparable for the two IV regimens when theentire pharmacokinetic sampling period was considered. For example, themean Css for O-desmethyltramadol was 86.6 ng/mL for 75 mg IV q6h and88.9 ng/mL for 50 mg IV q4h; the mean Css for 100 mg PO q6h was higher,at 128 ng/mL. This is understandable taking into account the similarityin the total IV doses administered in the study (650 mg for the 50 mg IVq4h arm, 675 mg for the 75 mg IV q6h arm) and the slightly higher oraldose (800 mg for the 100 mg PO q6h arm).

The observed mean (STD) tramadol plasma concentration versus time curvefor IV 50 mg and oral 100 mg as well as the fitted curve for the oral100 mg for the initial 12 hours after administration is presented inFIG. 11. The fitted curve was obtained because the second oral peak wasnot measured in the study. The model fit was very good (as can bevisually assessed in the figure), with the curve demonstrating theconcentrations of the IV 50 mg regimen are generally higher after theHour 2 dose. FIG. 12 illustrates that the 50 mg IV regimen is very closeto steady-state after the 3rd dose, due to the loading dose strategy(comparable Cmax after the hour 4 dose to Cmax after the Hour 44 dose),and that the oral Cmax is achieved later but reaches a similar level tothe 50 mg IV regimen.

Plasma pharmacokinetic parameters for tramadol in Example 5 are setforth in Table 11 below:

TABLE 11 75 mg IV 50 mg IV 100 mg Oral Parameter n Mean SD CV % n MeanSD CV % n Mean SD CV % T_(max) (h) 14 15.93 17.36 108.96 14 30.02 19.8966.27 17 44.03 1.01 2.29 C_(max) (ng/mL) 14 932 199 21.30 14 736 15220.60 17 701 178 25.44 C_(1 h) (ng/mL) 14 361 63.8 17.65 14 243 45.218.56 17 278 77.0 27.72 C₂ (ng/mL) — — — — 14 203 31.6 15.59 — — — — C₃(ng/mL) 14 237 41.6 17.53 — — — — — — — — C₆ (ng/mL) — — — — — — — — 17197 55.0 27.93 T_(max(0-2)) (h) — — — — 14 0.54 0.22 40.34 — — — —C_(max(0-2)) (ng/mL) — — — — 14 294 68.5 23.27 — — — — T_(max(0-3)) (h)14 0.50 0.28 55.47 — — — — — — — — C_(max(0-3)) (ng/mL) 14 484 155 31.93— — — — — — — — T_(max(0-6)) (h) — — — — — — — — 17 1.54 0.33 21.60C_(max(0-6)) (ng/mL) — — — — — — — — 17 377 68.9 18.31 T_(max(2-4)) (h)— — — — 14 2.36 0.13 5.40 — — — — C_(max(2-4)) (ng/mL) — — — — 14 47977.7 16.23 — — — — T_(max(3-6)) (h) 14 3.31 0.11 3.19 — — — — — — — —C_(max(3-6)) (ng/mL) 14 756 141 18.65 — — — — — — — — T_(max(42-48)) (h)14 42.38 0.19 0.45 — — — — 17 44.03 1.01 2.29 C_(max(42-48)) (ng/mL) 14827 234 28.24 — — — — 17 701 178 25.44 T_(max(44-48)) (h) — — — — 1444.30 0.11 0.24 — — — — C_(max(44-48)) (ng/mL) — — — — 14 711 152 21.40— — — — C₄₈ (ng/mL) 14 354 85.9 24.31 14 448 131 29.36 17 497 144 29.09AUC_(tau 1) (h*ng/mL) 14 1251 165.4 13.22 15 624.2 85.06 13.64 17 1494282.3 18.90 AUC₀₋₂₄ (h*ng/mL) 14 9932 1958 19.72 14 9520 2106 22.12 177491 1936 25.85 AUC₂₄₋₄₈ (h*ng/mL) 14 9402 2511 26.71 14 11020 285225.88 17 11650 3387 29.07 AUC₀₋₄₈ (h*ng/mL) 14 19330 4427 22.90 14 205404906 23.89 17 19140 5172 27.02 AUC_(tau n) (h*ng/mL) 14 3036 608.3 20.0414 2228 525.6 23.60 17 3475 902.2 25.97 RAC(C_(max)) 14 1.7828 0.497527.91 14 2.4663 0.4953 20.08 17 1.8588 0.2858 15.37 RAC_((trough)) 141.5026 0.3613 24.05 14 2.1937 0.4768 21.74 17 2.5580 0.4577 17.89RAC(AUC_(tau)) 14 2.4314 0.4060 16.70 14 3.5359 0.4662 13.18 17 2.32110.3437 14.81 Css (ng/mL) 14 506 101 20.03 14 557 131 23.60 17 579 15025.96 P/T Ratio First 14 2.0658 0.6131 29.68 14 1.4566 0.2812 19.31 171.9824 0.3664 18.48 P/T Ratio Last 14 2.3692 0.5090 21.48 14 1.63700.2655 16.22 17 1.4400 0.2286 15.87

Further data obtained concerning the pharmacokinetics of the 50 mg IVregimen from this study are as follows: the mean Cmax after the firstdose was about 273±60 ng/mL; the mean Cmax after the second dose wasabout 451±65 ng/mL; and the mean Cmax concentration after administrationof the third administered dose was about 666 ng/mL±135. The mean Cmaxconcentration after administration of the third administered dose ofabout 666 ng/mL±135 was similar to the steady-state Cmax of about 701ng/mL±178 obtained by a dosing regimen of 100 mg tramadol HCladministered orally every 6 hours, and was similar to mean C_(max) atsteady-state of about 736 ng/mL±152 obtained for the 50 mg IV regimen.

Plasma pharmacokinetic parameters of the O-desmethyltramadol metabolitein the study of Example 5 are set forth in Table 12:

TABLE 12 75 mg IV 50 mg IV 100 mg Oral Parameter n Mean SD CV % n MeanSD CV % n Mean SD CV % T_(max) (h) 14 32.99 16.50 50.01 14 44.95 1.593.53 17 43.97 1.12 2.54 C_(max) (ng/mL) 14 99.2 25.6 25.85 14 96.6 24.525.35 17 146 37.4 25.62 C_(1 h) (ng/mL) 14 19.9 6.65 33.32 14 11.8 4.5738.82 17 41.4 19.7 47.47 C₂ (ng/mL) — — — — 14 16.9 6.47 38.32 — — — —C₃ (ng/mL) 14 29.5 10.0 33.87 — — — — — — — — C₆ (ng/mL) — — — — — — — —17 42.3 13.6 32.19 T_(max(0-2)) (h) — — — — 14 1.85 0.19 10.34 — — — —C_(max(0-2)) (ng/mL) — — — — 14 17.1 6.46 37.91 — — — — T_(max(0-3)) (h)14 2.71 0.49 18.03 — — — — — — — — C_(max(0-3)) (ng/mL) 14 29.7 10.234.28 — — — — — — — — T_(max(0-6)) (h) — — — — — — — — 17 2.04 0.8742.42 C_(max(0-6)) (ng/mL) — — — — — — — — 17 60.3 22.7 37.60T_(max(2-4)) (h) — — — — 14 3.95 0.00 0.00 — — — — C_(max(2-4)) (ng/mL)— — — — 14 37.8 15.5 40.86 — — — — T_(max(3-6)) (h) 14 5.81 0.52 8.98 —— — — — — — — C_(max(3-6)) (ng/mL) 14 59.4 18.6 31.34 — — — — — — — —T_(max(42-48)) (h) 14 43.10 0.36 0.84 — — — — 17 43.97 1.12 2.54C_(max(42-48)) (ng/mL) 14 96.7 25.1 25.99 — — — — 17 146 37.4 25.62T_(max(44-48)) (h) — — — — 14 45.31 0.68 1.50 — — — — C_(max(44-48))(ng/mL) — — — — 14 96.2 24.5 25.46 — — — — C₄₈ (ng/mL) 14 75.9 22.429.48 14 81.7 20.2 24.68 17 111 31.5 28.33 AUC_(tau 1) (h*ng/mL) 14108.3 35.79 33.06 15 39.93 15.89 39.77 17 272.1 97.32 35.77 AUC₀₋₂₄(h*ng/mL) 14 1608 428.2 26.63 14 1425 405.4 28.44 17 1655 476.6 28.79AUC₂₄₋₄₈ (h*ng/mL) 14 1896 524.5 27.66 14 2002 514.9 25.72 17 2693 750.027.85 AUC₀₋₄₈ (h*ng/mL) 14 3504 931.2 26.58 14 3427 889.9 25.97 17 43491139 26.20 AUC_(tau n) (h*ng/mL) 15 519.8 142.7 27.45 14 355.6 89.3925.14 17 768.4 209.4 27.26 RAC(C_(max)) 14 3.4575 0.8063 23.32 14 6.07941.4574 23.97 17 2.7316 1.2718 46.56 RAC_((trough)) 14 2.7237 0.700025.70 14 5.2872 1.4637 27.68 17 2.7839 1.0135 36.41 RAC(AUC_(tau)) 145.0884 1.2051 23.68 14 9.7100 2.6019 26.80 17 3.1287 1.5078 48.19 Css(ng/mL) 14 86.6 23.8 27.44 14 88.9 22.3 25.14 17 128 34.9 27.25 P/TRatio First 14 1.0049 0.0185 1.84 14 1.0122 0.0327 3.23 17 1.3982 0.189013.52 P/T Ratio Last 14 1.2878 0.1073 8.33 14 1.1782 0.0772 6.55 171.3302 0.1635 12.29 M/P Ratio C_(1 h) 14 0.0571 0.0232 40.64 14 0.05030.0224 44.54 17 0.1579 0.0798 50.54 M/P Ratio T₄₈ 14 0.2266 0.0796 35.1414 0.2002 0.0794 39.67 17 0.2423 0.0929 38.33

The term “STD” as used herein means standard deviation. The term “C₂”means plasma concentration of tramadol at time 2 or hour 2 (in otherwords, the tramadol plasma concentration at 2 hours after the firstadministered tramadol dose). The term “C₃” means plasma concentration oftramadol at time 3 or hour 3 (in other words, the tramadol plasmaconcentration at 3 hours after the first administered tramadol dose).The term “C6” as used herein means plasma concentration of tramadol attime 6 or hour 6 (in other words, the tramadol plasma concentration at 6hours after the first administered tramadol dose). The term “C₄₈” asused herein means plasma concentration of tramadol at time 48 or hour 48(in other words, the tramadol plasma concentration at 48 hours after thefirst administered tramadol dose). The term “C_(ss)” means steady-stateconcentration. The term “C_(max)” means maximum concentration. The term“AUC” means area under the curve. The term “AUC_(tau)” means area underthe plasma concentration-time curve over the dosing interval. As opposedto AUC_((0-inf)) which is extrapolated out to infinity, AUC_(tau n) isthe AUC in the last dosing interval (for example, with respect to the 50mg dosing regimen, that would be at 44-48 hours from first dose). Theterm “RAC” means ratio of accumulation from first dose to steady-state.(Thus, if a patient had a C_(max) of 500 ng/ml in the first interval,and 1000 ng/mL at steady-state, the RAC is 1000/500=2.0). The term “P/T”means peak to trough. The term “M/P” means metabolite to parent(tramadol) ratio.

The mean tramadol C_(max) for the first dose ranged from 294 ng/mL after50 mg IV (C_(max(0-2))) to 484 ng/mL after 75 mg IV (C_(max(0-3))); theCmax after the first 100 mg PO (C_(max(0-6))) was 377 ng/mL. Over theentire pharmacokinetic sampling period, the C_(max) for 75 mg IV q6h wassomewhat higher, 932 ng/mL, compared to the other treatments. TheC_(max) after 50 mg IV q4h and 100 mg PO q6h were similar, at 736 ng/mLand 701 ng/mL, respectively. Of particular note, the C_(max) atsteady-state for 50 mg IV was 711 ng/ml, while for the oral dose it was701 ng/mL.

The higher peak concentrations for 75 mg IV q6h was reflected in thefluctuation between the peak and trough concentration; the P/T Ratiosfor the first and last doses of 75 mg IV q6h were larger (2.0658 to2.3692) than those observed for 50 mg IV q4h (1.4566 to 1.6370) and 100mg PO q6h (1.4400 to 1.9824). This result was expected, consideringlonger 6-hour dosing interval for the 75 mg IV treatment, compared tothe 50 mg IV treatment, and more time for drug elimination prior tosubsequent dosing.

During the last 24-hour sampling period (AUC₂₄₋₄₈), the exposure totramadol after 100 mg PO q6h (11650 h*ng/mL) was comparable to thatafter 50 mg IV q4h (11020 h*ng/mL); the AUC₂₄₋₄₈ for 75 mg IV q6h wassomewhat lower (9932 h*ng/mL). Two additional AUCs were calculated atthe time of pharmacokinetic analysis, AUC_(tau 1) (the AUC during thefirst dosing interval) and AUC_(tau n) (the AUC during the last dosinginterval). AUC_(tau 1) and AUC_(tau n) were used to provide anothermeasure of the accumulation during multiple dosing. AUC_(tau n) was usedto characterize the exposure at steady-state during a consistentregimen. Although AUC_(tau n) cannot be compared directly across alltreatments, due to the different dosing intervals of 4 or 6 h, theseAUCs can be used to estimate systemic exposure over a given multiple ofthese intervals, such as 12 h. The predicted exposure over 12 h atsteady sate was comparable for 50 mg IV q4h (3×2228=6684 h*ng/mL) and100 mg PO q6h (2×3475=6950 h*ng/mL), but somewhat lower for 75 mg IV q6h(2×3036=6072 h*ng/mL). These values correlate well with the averageconcentration at steady-state (Css), at 557 ng/mL and 579 ng/mL for 50mg IV q4h and 100 mg PO q6h, respectively, and 506 ng/mL for 75 mg IVq6h.

The accumulation factors for tramadol ranged from 1.5026 to 2.4314 for75 mg IV q6h, from 2.1937 to 3.5359 for 50 mg IV q4h, and from 1.8588 to2.5580 for 100 mg PO q6h. Overall, these values are in good agreementwith the theoretical accumulation factors of 1.82 for a 6-h dosinginterval and 2.42 for a 4-h dosing interval, calculated as 1/[1−exp(−ln2*tau/T_(1/2))] and using T_(1/2) of approximately 5.2 h). The shorterdosing interval results in a higher degree of accumulation atsteady-state, relative to the concentrations observed after the firstdose, but less fluctuation in the concentrations during the dosinginterval.

The 75 mg IV/100 mg PO ratios ranged from 74.67 to 137.94%, indicatinghigher exposure to tramadol after 75 mg IV q6h compared to 100 mg PO q6hin general, most apparent through 24 hours. Based on the 80.00-125.00%acceptance criteria for the 90% confidence intervals, AUC₀₋₄₈ was notsignificantly different between these treatments. The 50 mg IV/100 mg POratios ranged from 89.82 to 127.81%, and only AUC₀₋₂₄ had 90% confidenceintervals outside the 80.00-125.00% range; C_(max), AUC₂₄₋₄₈, AUC₀₋₄₈,and T₄₈ were not significantly different between these treatments. The75 mg IV/50 mg IV ratios ranged from 83.13 to 129.16%; although the AUCswere not significantly different across these treatments, the C_(max)and T₄₈ concentrations were, reflecting the more pronounced fluctuationin tramadol concentrations for the 75 mg IV q6h arm.

Exposure to O-desmethyltramadol was higher after 100 mg PO q6h comparedto either IV treatment, 50 mg IV q4h or 75 mg IV q6h. This was expected,considering the first pass metabolism after oral administration.Although exposure parameters were slightly higher for 75 mg IV q6hcompared to 50 mg IV q4h through early time points, exposure toO-desmethyltramadol was comparable for the two IV regimens when theentire pharmacokinetic sampling period was considered. For example, themean Css for O-desmethyltramadol was 86.6 ng/mL for 75 mg IV q6h and88.9 ng/mL for 50 mg IV q4h; the mean Css for 100 mg PO q6h was higher,at 128 ng/mL. This is understandable taking into account the similarityin the total IV doses administered in the study (650 mg for the 50 mg IVq4h arm, 675 mg for the 75 mg IV q6h arm) and the slightly higher oraldose (800 mg for the 100 mg PO q6h arm).

The following conclusions are drawn from Example 5: (1) the 50 mg IVregimen, as compared to the 75 mg IV regimen, resulted in less peak totrough fluctuation with lower Cmax. This regimen also provided apharmacokinetic profile very similar to the 100 mg oral dose regimen;and (2) exposure to O-desmethyltramadol was higher after 100 mg PO q6hcompared to either IV treatment, 50 mg IV or 75 mg IV regimens, based onAUC and Cmax values; (3) overall Cmax was comparable between the 50 mgIV and 100 mg PO regimens; exposure at steady-state to tramadol, basedon Cmax and AUC, was also comparable between 50 mg IV q4h and 100 mg POq6h; (4) administration of a lower IV dose more frequently, as in the 50mg IV q4h regimen compared to the 75 mg IV q6 regimen, resulted in lessfluctuation during the dosing interval and a pharmacokinetic profilevery similar to the 100 mg oral dose; (5) compared to the 50 mg IV q4hand 100 mg PO q6h regimens, greater peak to trough variance in tramadolconcentrations was observed for the 75 mg IV q6h regimen. The data fromExample 5 demonstrate that the 50 mg IV dosing regimen (with tramadol 50mg at Hour 0, followed by 50 mg at Hour 2, 50 mg at hour 4, and 50 mgevery 4 hours thereafter through Hour 44) provides a preferred result.

CONCLUSION

All patents and publications identified in the above paragraphs arehereby incorporated by reference in their entireties. It will be readilyapparent to one of ordinary skill in the relevant arts that othersuitable modifications and adaptations to the methods and applicationsdescribed herein are suitable and may be made without departing from thescope of the invention or any embodiment thereof. While the inventionhas been described in connection with certain embodiments, it is notintended to limit the invention to the particular forms set forth, buton the contrary, it is intended to cover such alternatives,modifications and equivalents as may be included within the spirit andscope of the invention as defined by the following claims. All of thepatents and publications cited herein are hereby incorporated byreference.

1-27. (canceled)
 28. A method of administering tramadol for treatingacute pain in a human patient via an intravenous dosing regimen,comprising intravenously administering a first dose of tramadol to ahuman patient experiencing acute pain in an amount of about 50 mg; andthereafter intravenously administering additional doses of tramadol tothe human patient(s) in an amount of about 50 mg tramadol at dosageintervals of about 4 hours, except that a second dose is intravenouslyadministered as a loading dose at a shortened interval as compared tothe dosage interval of about 4 hours, such that a total of 7 doses of 50mg tramadol are intravenously administered on the first day of treatmentand the intravenous tramadol is administered on subsequent days oftreatment on a basis of a total of 6 doses of 50 mg tramadol per dayuntil the intravenous tramadol administration is terminated, and whereinthe tramadol is tramadol base or a pharmaceutically acceptable salt oftramadol, such that the mean Cmax concentration after administration ofthe third administered dose of tramadol is similar to the mean C_(max)at steady-state and is similar to the mean Cmax at steady-state for adosing regimen of 100 mg tramadol HCl administered orally every 6 hours,and such that the intravenous dosing regimen provides a steady-stateCmax and AUC of tramadol which is similar to the steady-state Cmax andAUC of 100 mg tramadol HCl given every 6 hours.
 29. The method of claim28, further comprising continuing to administer additional doses oftramadol to the human patient in an amount of about 50 mg tramadol atdosage intervals of about 4 hours for at least about 44 hours after thefirst administered dose of tramadol.
 30. The method of claim 28, furthercomprising continuing to administer additional doses of tramadol to thehuman patient in an amount of about 50 mg tramadol at dosage intervalsof about 4 hours for at least about 44 hours after the firstadministered dose of tramadol, such that the intravenous dosing regimenprovides a Cmax of tramadol at steady-state of about 711 ng/mL±152. 31.The method of claim 28, further comprising continuing to administeradditional doses of tramadol to the human patient in an amount of about50 mg tramadol at dosage intervals of about 4 hours for at least about24 hours after the first administered dose of tramadol, such that theintravenous dosing regimen provides an AUC₀₋₂₄ of about 9520h*ng/ml±2106.
 32. The method of claim 28, further comprising continuingto administer additional doses of tramadol to the human patient in anamount of about 50 mg tramadol at dosage intervals of about 4 hours forat least about 44 hours after the first administered dose of tramadol,such that the intravenous dosing regimen provides an AUC₀₋₄₈ of about20,540 h*ng/ml±4906.
 33. The method of claim 28, wherein the humanpatient is experiencing acute post-operative pain.
 34. A method ofadministering tramadol for treating acute pain in a human patient via anintravenous dosing regimen, comprising intravenously administering afirst dose of tramadol to a human patient experiencing acute pain in anamount of about 50 mg; and thereafter intravenously administeringadditional doses of tramadol to the human patient(s) in an amount ofabout 50 mg tramadol at dosage intervals of about 4 hours, except that asecond dose is intravenously administered as a loading dose at ashortened interval as compared to the dosage interval of about 4 hours,such that a total of 7 doses of 50 mg tramadol are intravenouslyadministered on the first day of treatment and the intravenous tramadolis administered on subsequent days of treatment on a basis of a total of6 doses of 50 mg tramadol per day until the intravenous tramadoladministration is terminated, and wherein the tramadol is tramadol baseor a pharmaceutically acceptable salt of tramadol, such that the meanCmax concentration after administration of the third administered doseof tramadol is similar to the mean C_(max) at steady-state and issimilar to the mean Cmax at steady-state for a dosing regimen of 100 mgtramadol HCl administered orally every 6 hours, and such that theintravenous dosing regimen provides a steady-state Cmax and an AUC₀₋₄₈of tramadol which is similar to the steady-state Cmax and AUC₀₋₄₈ of anoral dose of 100 mg tramadol HCl given every 6 hours, wherein thetramadol is tramadol base or a pharmaceutically acceptable salt oftramadol.
 35. The method of claim 33, further comprising continuing toadminister additional doses of tramadol to the human patient in anamount of about 50 mg tramadol at dosage intervals of about 4 hours forat least about 44 hours after the first administered dose of tramadol.36. The method of claim 33, further comprising continuing to administeradditional doses of tramadol to the human patient in an amount of about50 mg tramadol at dosage intervals of about 4 hours for at least about44 hours after the first administered dose of tramadol, such that theintravenous dosing regimen provides a Cmax of tramadol at steady-stateof about 711 ng/ml±152.
 37. The method of claim 33, further comprisingcontinuing to administer additional doses of tramadol to the humanpatient in an amount of about 50 mg tramadol at dosage intervals ofabout 4 hours for at least about 24 hours after the first administereddose of tramadol, such that the intravenous dosing regimen provides anAUC₀₋₂₄ of about 9520 h*ng/ml±2106.
 38. The method of claim 33, furthercomprising continuing to administer additional doses of tramadol to thehuman patient in an amount of about 50 mg tramadol at dosage intervalsof about 4 hours for at least about 44 hours after the firstadministered dose of tramadol, such that the intravenous dosing regimenprovides an AUC₀₋₄₈ of about 20,540 h*ng/ml±4906.
 39. A method ofadministering tramadol for treating acute postoperative pain in a humanpatient via an intravenous dosing regimen, consisting of intravenouslyadministering a first dose of tramadol to a human patient experiencingacute postoperative pain in an amount of about 50 mg; and thereafterintravenously administering additional doses of tramadol to the humanpatient(s) in an amount of about 50 mg tramadol at dosage intervals ofabout 4 hours, except that a second dose is intravenously administeredas a loading dose at a shortened interval as compared to the dosageinterval of about 4 hours, a total of 7 doses of 50 mg tramadol beingintravenously administered on the first day of treatment and theintravenous tramadol being administered on subsequent days of treatmenton a basis of a total of 6 doses of 50 mg tramadol per day until theintravenous tramadol administration is terminated, and wherein thetramadol is tramadol base or a pharmaceutically acceptable salt oftramadol, such that such that the mean Cmax after the first dose isabout 273±60 ng/mL, the mean Cmax after the second dose is about 451±65ng/mL, and the mean Cmax concentration after administration of the thirdadministered dose of tramadol is about 666 ng/mL±135 and the mean Cmaxat steady-state is of about 711 ng/mL±152, such that the intravenousdosing regimen provides a steady-state Cmax of about 711±152 ng/ml and aC_(ss) of about 557±131 ng/ml, wherein the tramadol is tramadol base ora pharmaceutically acceptable salt of tramadol.
 40. The method of claim38, further comprising continuing to administer additional doses oftramadol to the human patient in an amount of about 50 mg tramadol atdosage intervals of about 4 hours for at least about 44 hours after thefirst administered dose of tramadol.
 41. The method of claim 38, furthercomprising continuing to administer additional doses of tramadol to thehuman patient in an amount of about 50 mg tramadol such that theintravenous dosing regimen provides an AUC₀₋₂₄ of about 9520h*ng/ml±2106.
 42. The method of claim 38, further comprising continuingto administer additional doses of tramadol to the human patient in anamount of about 50 mg tramadol at dosage intervals of about 4 hours forat least about 44 hours after the first administered dose of tramadol,such that the intravenous dosing regimen provides an AUC₀₋₄₈ of about20,540 h*ng/ml±4906.